Compounds containing polysubstituted benzo[d][1,3]oxathiole, benzo[d][1,3]oxathiole 3-oxide or benzo[d][1,3]oxathiole 3,3-dioxide and methods/uses thereof as agonists of g protein-coupled receptor 119

ABSTRACT

There are provided compounds having formula (I), in which: X 1  and X 2  are selected from certain combinations of O, S, SO and SO 2 ; X 3  is selected from CH, CF and N; X 4  is selected from CH and N; X 6 , X 6′  and X 6″  are selected from H, halogen, and certain alkyl, haloalkyl, alkoxy, hydroxyalkyl, and amide groups; X 7  and X 7′  are selected from H, halogen, and certain alkyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl and amide groups, or both X 7  and X 7′  together form a cycloalkyl or heterocycle; and A is selected from certain optionally substituted, alkoxy, piperazinyl and pyrrolidinyl groups. Also provided are compositions comprising these compounds, as well as uses/methods related thereto, including treatment of diseases and conditions associated with GPR119 dysregulation, Type 2 diabetes mellitus, and related metabolic disorders. (I)

FIELD OF INVENTION

The present invention relates to polysubstitutedbenzo[d][1,3]oxathioles, benzo[d][1,3]oxathiole 3-oxides,benzo[d][1,3]oxathiole 3,3-dioxides, and related compounds andpharmaceutical compositions comprising the compounds, as well as usesand methods related thereto.

BACKGROUND OF THE INVENTION

Insulin is a hormone that regulates blood sugar produced by thepancreas. Diabetes is a chronic disease that occurs either when thepancreas does not produce enough insulin or when the body cannoteffectively use the insulin it produces. Hyperglycemia, or raised bloodsugar, is a common effect of uncontrolled diabetes and over time leadsto serious damage to many of the body's systems, especially the nervesand blood vessels. The global prevalence of diabetes is estimated to beover 9% of adults aged 18+ years, corresponding to about 2-fold increasein the last ten years. There are three types of diabetes: Type 1 alsoknown as insulin-dependent or juvenile requires daily administration ofinsulin. Type 2 diabetes (T2DM) also known as non-insulin dependentdiabetes mellitus results from the body's ineffective use or ability toregulate insulin. Gestational diabetes is a condition where the bloodglucose values are above normal but below those characteristic ofdiabetes occurring during pregnancy. Diabetes increases the risk ofheart failure, stroke, neuropathy in the feet, retinopathy which is animportant cause of blindness and kidney failure.

Several therapies for T2DM have been used in patients and include: 1)glucose-lowering effectors, such as metformin which reduces glucoseproduction from the liver; 2) insulin or insulin secretagogues, such assulphonylureas, which increase insulin production from pancreaticβ-cells; 3) activators of the peroxisome proliferator-activatedreceptor-γ (PPAR-γ), such as the thiazolidinediones, which enhanceinsulin action; 4) α-glucosidase inhibitors which interfere with gutglucose production; 5) Glucagon-like peptide 1 (GLP-1) analogs, 6)sodium glucose transporter 2 inhibitors (SGLT2) and 7) dipeptidylpeptidase 4 (DPP-IV) inhibitors (DeFronzo, R. A. et al. DiabetesSpectrum 2014, 27, 100-112). Other potential therapeutics underinvestigation include glucagon receptor antagonists, glucokinaseactivators, fructose-1,6-bisphosphatase inhibitors, acetyl-CoAcarboxylase inhibitors, bile acids sequestrates, activators of bile acidfarnesoid X receptor and AMPK activators (Vangaveti, V. et al. Ther.Adv. Endocrin. Metabol. 2010, 1, 165-175), G-protein coupled receptors139 and 142 and somatostatin receptor 3 antagonists. There are, however,deficiencies associated with currently available treatments, includingedema, weight gain, hypoglycemic episodes, and a relatively highfrequency of gastrointestinal side effects Small molecule DPP-4inhibitors enhance glucose-dependent insulin release by inhibiting thedegradation of endogenous GLP-1.

The G protein-coupled receptor 119 (GPR119) is a class A(rhodopsin-type) orphan GPCR without close primary sequence relative inthe human genome (Shah, U. et al. Vitam. Horm., 2010, 84, 415-448). Itis expressed on L- and K-cells in intestine and on β cells in thepancreas and foetal liver. GPR119 homologs have been identified inseveral vertebrate species, including rodents (rat, mice, and hamster),chimpanzee, rhesus monkey, cattle and dog (Davey, J. Exp. Opin. Ther.Targ. 2004, 8, 165-170). High-level expression of GPR119 in cells led toan increase in intracellular cAMP levels via activation of adenylatecyclase (Chu, Z. L. et al. Endocrin. 2007, 148, 2601-2609), indicatingthat this receptor couples efficiently to Gα_(s). GPR119 stimulates therelease of several key molecules: 1) GIP, a major insulinotropic hormoneof the gut, produced primarily in the duodenal K cells, 2) GLP-1 and 3)at least one other L-cell peptide, peptide YY (3-36) (PYY) (Chu, Z. L.et al. Endocrin. 2008, 149, 2038-2047).

These findings validate GPR119 receptor as a biological target foragonist development that can be potentially used as therapeutics inT2DM, obesity and metabolic syndrome treatment. Many agents have beendisclosed as potent agonists (Ritter, K. et al. J. Med. Chem. 2016, 59,3579-3592), with activity in rodents including APD668, APD597(WO05121121) (Semple, G. et al. Bioorg. Med. Chem. Lett. 2012, 22,1750-1755), PSN-821 (Fyfe, M. WO2009050522), HD047703 (Kim, S. et al.Biomol. Ther. 2014, 22, 400-405), AS1669058 (Oshima, H. et al. Life Sci.2013, 92, 167-173), AS1535907 (Yoshida, S. et al. Diabetes, ObesityMetabol. 2011, 13, 34-41).

Sulphone containing agonists include GSK-1292263 (Zhu et al. Eur. J.Med. Chem. 2011, 46, 2901-2907) and BMS-903452 (Wacker, D. A. et al. J.Med. Chem. 2014, 57, 7499-7508),

MBX-2982 is a a tetrazole containing GPR agonist lacking the sulphonefunctional group (Jones, R. M. et al. Expert Opin. Ther. Pat. 2009, 19,1339-1359).

Russian patent application RU2576037C1 discloses substituted1,3-benzoxathioles as GPR119 receptor agonists where R is H, C₁-C₅alkyl, halogen-substituted C₁-C₅ alkyl, acyl selected from the groupC₁-C₅ alkyl(C═O) and phenyl(C═O), substituted heteroaryl representing anaromatic monocyclic group with two nitrogen atoms which is substitutedby a halogen atom or (C₁-C₅) alkyl, (C₁-C₃) alkylsulphonyl,phenylsulphonyl; R¹, R², R³, R⁴ represent hydrogen or one or twosubstitutents simultaneously selected from a halogen, (C₁-C₃)alkyl,halogen-substituted (C₁-C₃)alkylsulphonyl and a cyano group.

To date, disease and conditions associated with dysregulation of GPR119such as T2DM, diabetes-mediated diseases and conditions, and metabolicdisorders remain a major health concern. There is a clear and presentneed to identify additional compounds capable of modulating GPR119activity as well as compounds that are therapeutically useful for thetreatment of disease and conditions associated with dysregulation ofGPR119 such as T2DM, diabetes-mediated diseases and conditions, andmetabolic disorders.

BRIEF SUMMARY OF THE INVENTION

Various embodiments of the present invention relate to a compound havingformula (I):

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (I), or a prodrug or complex thereof,wherein:X¹ is O and X² is S, SO or SO₂; or X² is O and X¹ is S, SO or SO₂;

X³ is CH, CF and N;

each X⁴ is independently CH and N;

A is

R is

R¹ is hydrogen, C(O)O-tert-butyl or

R^(2a) is hydrogen or C₁₋₆ alkyl;R^(2b) is hydrogen or C₁₋₆ alkyl;R³ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b), CH₂C(O)OR^(10a),

R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b),

R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b),

R⁶ is

NHR¹¹ or CH₂NHR¹²;R^(7a) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxy;R^(7b) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxy;R^(7c) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxy;R⁸ is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl or C₃₋₇cycloalkyl;R⁹ is C₁₋₆ alkyl, C₃₋₇ branched alkyl or

R¹⁰ is C₁₋₆ alkyl or C₃₋₇ branched alkyl;R^(10a) is hydrogen, C₁₋₆ alkyl or C₃₋₇ branched alkyl;R^(10b) is hydrogen, C₁₋₆ alkyl or C₃₋₇ branched alkyl;

R¹¹ is

R¹² is

each R^(13a) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇ branchedalkyl;each R^(13b) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇ branchedalkyl;each R^(14a) is independently hydrogen, C₁₋₆ alkyl, C₃₋₇ branched alkylor C(O)O-tert-butyl;each R^(14b) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇ branchedalkyl;X⁵ is N or CR^(7b);n1 is 1 or 2;n2 is 1 or 2;and m is 1, 2, 3, 4, 5, 6 or 7;each of X⁶, X^(6′) and X^(6″) is independently H, halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, orC₁₋₃(O)NR^(15a)R^(15b);each of X⁷ and X^(7′) is independently hydrogen, halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl orC₁₋₃(O)NR^(15a)R^(15b), or both X⁷ and X^(7′) together form C₃₋₆cycloalkyl or a heterocycle ring having 3-6 carbons and 0 or 1 oxygen,sulphur or nitrogen atom in the ring, wherein each carbon ring atom ofthe C₃₋₆ cycloalkyl or the heterocycle is independently substituted withhydrogen, C₁₋₃ alkyl, hydroxyl, halogen, amino, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ hydroxyalkyl or C₁₋₃(O)NR^(15a)R^(15b);when each of X⁶, X^(6′) and X^(6″) is hydrogen, at least X⁷ or X^(7′) isnot hydrogen;when both X⁷ and X^(7′) are hydrogen, at least one of X⁶, X^(6′) andX^(6″) is not hydrogen; andeach of R^(15a) and R^(15b) is independently hydrogen, C₁₋₃ alkyl or C₃branched alkyl.

In some embodiments, the compound excludes any compound having formula(Ia)

wherein:X⁶, X^(6′), X^(6″), X⁷ and X^(7′) are as defined for any embodimentsdefined herein;R¹⁵ is: hydrogen; C₁-C₅ alkyl; halogen-substituted C₁-C₅ alkyl; acylselected from the group C₁-C₅ alkyl(C═O) and phenyl(C═O); substitutedheteroaryl representing a monocyclic aromatic group with two nitrogenatoms which is substituted by a halogen or (C₁-C₅) alkyl; (C₁-C₃)alkylsulphonyl; or phenylsulphonyl; andR^(16a), R^(16b), R^(16c) and R^(16d) are hydrogen or one or twosubstitutents simultaneously selected from the group consisting ofhalogen, (C₁-C₃) alkyl, halogen-substituted (C₁-C₃)alkyl,(C₁-C₃)alkylsulphonyl or cyano.

In some embodiments, R³ is not C(O)OR¹⁰.

In some embodiments, one, two or three of X⁶, X^(6′) and X^(6″) arefluorine. In some embodiments, X⁶, X^(6′) and X^(6″) are: F, H and H,respectively; H, F and H, respectively; or H, H and F, respectively. Insome embodiments, X⁶, X^(6′) and X^(6″) are each H.

In some embodiments, both of X⁷ and X^(7′) are hydrogen. In someembodiments, both of X⁷ and X^(7′) are CH₃. In some embodiments, atleast one of X⁷ and X^(7′) is halogen.

In some embodiments, the compound has formula (II) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (II), or a complex thereof:

In some embodiments, the compound has formula (III) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (III), or a complex thereof:

In some embodiments, the compound has formula (IV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (IV), or a complex thereof:

In some embodiments, the compound has formula (V) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (V), or a complex thereof:

wherein X⁸ is NH or O.

In some embodiments, the compound has formula (VI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (VI), or a complex thereof:

wherein: one X⁸ is NH or O; and one X⁸ is CH₂.

In some embodiments, the compound has formula (VII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (VII), or a complex thereof:

wherein: one X⁸ is NH or O; and each of two X⁸ is CH₂.

In some embodiments: X¹ is O and X² is SO₂; or X¹ is SO₂ and X² is O. Insome embodiments: X¹ is O and X² is SO; or X¹ is SO and X² is O. In someembodiments: X¹ is O and X² is S; or X¹ is S and X² is O. In someembodiments X¹ is O. In some embodiments X² is O.

In some embodiments, the compound has formula (VIII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (VIII), or a complex thereof:

In some embodiments, the compound has formula (IX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (IX), or a complex thereof:

In some embodiments, the compound has formula (X) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (X), or a complex thereof:

In some embodiments, the compound has formula (XI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XI), or a complex thereof:

In some embodiments, the compound has formula (XII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XII), or a complex thereof:

In some embodiments, the compound has formula (XIII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XIII), or a complex thereof:

In some embodiments, the compound has formula (XIV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XIV), or a complex thereof:

In some embodiments, the compound has formula (XV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XV), or a complex thereof:

In some embodiments, the compound has formula (XVI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XVI), or a complex thereof:

In some embodiments, the compound has formula (XVII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XVII), or a complex thereof

In some embodiments, the compound has formula (XVIII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XVIII), or a complex thereof:

In some embodiments, the compound has formula (XIX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XIX), or a complex thereof:

In some embodiments, the compound has formula (XX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XX), or a complex thereof:

In some embodiments, the compound has formula (XXI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXI), or a complex thereof:

In some embodiments, the compound has formula (XXII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXII), or a complex thereof:

In some embodiments, the compound has formula (XXIII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXIII), or a complex thereof:

In some embodiments, the compound has formula (XXIV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXIV), or a complex thereof:

In some embodiments, the compound has formula (XXV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXV), or a complex thereof:

In some embodiments, the compound has formula (XXVI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXVI), or a complex thereof:

In some embodiments, the compound has formula (XXVII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXVII), or a complex thereof:

In some embodiments, the compound has formula (XXVIII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXVIII), or a complex thereof:

In some embodiments, the compound has formula (XXIX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXIX), or a complex thereof:

In some embodiments, the compound has formula (XXX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXIX), or a complex thereof:

wherein, in alternative embodiments, X¹, X², X³, X⁴, R^(2a), R^(2b) andR³ are as defined for each entry in Table 1A and for each of the 80entries in Table 1A, X⁶, X^(6′), X^(6″), X⁷, X^(7′) are as defined foreach entry in Table 1B.

In some embodiments, X³ is CF or N.

Various embodiments of the present invention relate to a compound, whichis:5-chloro-2-(4-{[4-(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine;5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine;5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine;or5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine.

Various embodiments of the present invention relate to a composition(e.g. a pharmaceutical composition) comprising one or more compoundsdefined herein and an excipient (e.g. a pharmaceutically acceptableexcipient). The composition may further comprise an anti-diabetic agent.Various embodiments relate to a composition (e.g. a pharmaceuticalcomposition) comprising one or more compounds defined herein and ananti-diabetic agent.

Various embodiments of the present invention relate to an effectiveamount of one or more compounds defined herein and a treatment for atyrosine kinases-mediated disease or condition.

Various embodiments of the present invention relate to an effectiveamount of one or more compounds defined herein, a treatment for atyrosine kinases-mediated disease or condition, and an excipient.

Various embodiments of the present invention relate to a method fortreating or preventing diabetes-mediated diseases or conditions, such asType 2 diabetes mellitus as well as other diseases and related metabolicdisorders and conditions associated with GPR119 dysregulation, saidmethod comprising administering to a subject an effective amount ofcertain compound(s) or composition(s) defined herein. Variousembodiments of the present invention relate to use of certaincompound(s) defined herein for treating, or for manufacturing amedicament for treating, a disease or condition associated with GPR119dysregulation. The disease or condition may be Type 2 diabetes mellitus.

Various embodiments of the present invention relate to use of certaincompound(s) defined herein in in vitro assays for modulating GPR119receptor activity (e.g. as an agonist, whether as a full agonist or as apartial agonist). Various embodiments of the present invention relate touse of certain compound(s) defined herein in vivo assays for modulatingGPR119 receptor activity (e.g. as an agonist, whether as a full agonistor as a partial agonist).

DETAILED DESCRIPTION OF THE INVENTION

Certain novel benzo[d][1,3]oxathioles, benzo[d][1,3]oxathiole 3-oxides,benzo[d][1,3]oxathiole 3,3-dioxides and related compounds of the presentdisclosure are agonists of the GPR119 receptor (whether as full orpartial agonists). Accordingly, certain of these compounds are capableof treating and/or preventing diseases associated with GPR119dysregulation, for example Type 2 diabetes mellitus as well as otherdiseases and related metabolic disorders and conditions associated withGPR119 dysregulation. Certain GPR119 activity modulators (partial orfull agonists) of the present invention are capable of treating andpreventing diseases associated with dysregulation of GPR119 activity,for example Type 2 diabetes mellitus, diabetes-mediated diseases orconditions, and metabolic disorders. In addition, without wishing to belimited by theory, it is believed that certain compounds of thedisclosure can ameliorate, abate, otherwise cause to be controlled,diseases or conditions caused by GPR119 dysregulation.

I. Definitions

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings also consistessentially of, or consist of, the recited components, and that theprocesses of the present teachings also consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from a groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously.

Unless otherwise specified, “certain embodiments”, “variousembodiments”, “an embodiment” and similar terms includes the particularfeature(s) described for that embodiment either alone or in combinationwith any other embodiment or embodiments described herein, whether ornot the other embodiments are directly or indirectly referenced andregardless of whether the feature or embodiment is described in thecontext of a compound, method, product, use, composition, etcetera.

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and/or “aliphatic”whether used alone or as part of a substituent group refers to straightand branched carbon chains having 1 to 20 carbon atoms or any numberwithin this range, for example 1 to 6 carbon atoms or 1 to 4 carbonatoms. Designated numbers of carbon atoms (e.g. C₁₋₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groupscan be optionally substituted. Non-limiting examples of substitutedalkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl,aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl,3-carboxypropyl, and the like. In substituent groups with multiple alkylgroups such as (C₁₋₆alkyl)₂amino, the alkyl groups may be the same ordifferent.

As used herein, the terms “alkenyl” and “alkynyl” groups, whether usedalone or as part of a substituent group, refer to straight and branchedcarbon chains having 2 or more carbon atoms, preferably 2 to 20, whereinan alkenyl chain has at least one double bond in the chain and analkynyl chain has at least one triple bond in the chain. Alkenyl andalkynyl groups can be optionally substituted. Nonlimiting examples ofalkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, andthe like. Nonlimiting examples of substituted alkenyl groups include2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl,7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl,and the like. Nonlimiting examples of alkynyl groups include ethynyl,prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.Nonlimiting examples of substituted alkynyl groups include,5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl,5-hydroxy-5-ethylhept-3-ynyl, and the like.

As used herein, “cycloalkyl,” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused,bridged, and/or spiro ring systems), wherein the carbon atoms arelocated inside or outside of the ring system. Any suitable ring positionof the cycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl,decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens of an alkyl grouphave been replaced with halogens (e.g., —CF₃, —CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substituents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm C₃-C₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atomsand at least one oxygen atom (e.g., tetrahydrofuran,tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may besubstituted.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as a an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, wherethe alkyl and aryl groups are as defined herein. Aralkyl groups of thepresent invention are optionally substituted. Examples of arylalkylgroups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl,isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl,hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole,and 1,2,3,4-tetrahydroquinoline. Non-limiting examples of heterocyclicunits having 2 or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. Heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl,oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl,pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limitingexamples of heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, and isoquinolinyl.

One non-limiting example of a heteroaryl group as described above isC₁-C₅ heteroaryl, which has 1 to 5 carbon ring atoms and at least oneadditional ring atom that is a heteroatom (preferably 1 to 4 additionalring atoms that are heteroatoms) independently selected from nitrogen(N), oxygen (O), or sulfur (S). Examples of C₁-C₅ heteroaryl include,but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl,imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl,furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted.

For the purposes of the present disclosure fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be considered to belong to the cyclic familycorresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present disclosure, considered aheterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine having theformula:

is, for the purposes of the present disclosure, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the disclosure. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms of asingle moiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. The term “substituted” is used throughout thepresent disclosure to indicate that a moiety can have one or more of thehydrogen atoms replaced by a substituent. When a moiety is described as“substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl,cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groupsdefined herein, whether used alone or as part of another group, can beoptionally substituted. Optionally substituted groups will be soindicated.

The following are non-limiting examples of substituents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine (A-I)), —CN, —NO₂, oxo (═O),—OR¹⁵, —SR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(O)R¹⁵, —SO₂R¹⁵, —SO₂OR¹⁵, —SO₂N(R¹⁵)₂,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle,or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN, —NO₂, oxo, and R¹⁵; wherein R¹⁵, ateach occurrence, independently is hydrogen, —OR¹⁶, —SR¹⁶, —C(O)R¹⁶,—C(O)OR¹⁶, —C(O)N(R¹⁶)₂, —SO₂R¹⁶, —S(O)₂OR¹⁶, —N(R¹⁶)₂, —NRC(O)R¹⁶, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl (e.g.,C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R¹⁵ unitstaken together with the atom(s) to which they are bound form anoptionally substituted carbocycle or heterocycle wherein said carbocycleor heterocycle has 3 to 7 ring atoms; wherein R¹⁶, at each occurrence,independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, orheteroaryl, or two R¹⁶ units taken together with the atom(s) to whichthey are bound form an optionally substituted carbocycle or heterocyclewherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

-   -   i) —OR¹⁷; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;    -   ii) —C(O)R¹⁷; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;    -   iii) —C(O)OR¹⁷; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;    -   iv) —C(O)N(R¹⁷)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;    -   v) —N(R¹⁷)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);    -   vi) halogen: —F, —Cl, —Br, and —I;    -   vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2,        e+g=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   viii) —SO₂R¹⁷; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;    -   ix) C₁-C₆ linear, branched, or cyclic alkyl;    -   x) Cyano    -   xi) Nitro;    -   xii) N(R¹⁷)C(O)R¹⁷;    -   xiii) Oxo (═O);    -   xiv) Heterocycle; and    -   xv) Heteroaryl;        wherein each R¹⁷ is independently hydrogen, optionally        substituted C₁-C₆ linear or branched alkyl (e.g., optionally        substituted C₁-C₄ linear or branched alkyl), or optionally        substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄        cycloalkyl); or two R¹⁷ units can be taken together to form a        ring comprising 3-7 ring atoms. In certain embodiments, each R¹⁷        is independently hydrogen, C₁-C₆ linear or branched alkyl        optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆        cycloalkyl.

At various places in the present disclosure, substituents of compoundsare disclosed in groups or in ranges. It is specifically intended thatthe description include each and every individual subcombination of themembers of such groups and ranges. For example, the term “C₁₋₆ alkyl” isspecifically intended to individually disclose C₁, C₂, C₃, C₄, C₅, C₆,C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆,C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present disclosure the terms “compound,”“analog,” and “composition of matter” stand equally well for thecompounds of the disclosure described herein, including all enantiomericforms, diastereomeric forms, salts, and the like, and the terms“compound,” “analog,” and “composition of matter” are usedinterchangeably throughout the present disclosure.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastereomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with morpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄,Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, whena compound disclosed herein contains a basic moiety, salts can be formedusing organic and inorganic acids. For example, salts can be formed fromthe following acids: acetic, propionic, lactic, benzenesulfonic,benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic,ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic,mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g., in N(R¹⁶)₂, each R¹⁶ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The terms “treat” and “treating” and “treatment” as used herein, referto partially or completely alleviating, inhibiting, ameliorating and/orrelieving a condition from which a patient is suspected to suffer.

As used herein, “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention.

II. Compounds of the Invention

There are disclosed compounds having formula (I):

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (I), or a prodrug or complex thereof,wherein:X¹ is O and X² is S, SO or SO₂; or X² is O and X¹ is S, SO or SO₂;

X³ is CH, CF and N;

each X⁴ is independently CH and N;

A is

R is

R¹ is hydrogen, C(O)O-tert-butyl or

R^(2a) is hydrogen or C₁₋₆ alkyl;R^(2b) is hydrogen or C₁₋₆ alkyl;R³ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b), CH₂C(O)OR^(10a),

R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b),

R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b),

R⁶ is

NHR¹¹ or CH₂NHR¹²;R^(7a) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxy;R^(7b) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxy;R^(7c) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxy;R⁸ is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl or C₃₋₇cycloalkyl;R⁹ is C₁₋₆ alkyl, C₃₋₇ branched alkyl or

R¹⁰ is C₁₋₆ alkyl or C₃₋₇ branched alkyl;R^(10a) is hydrogen, C₁₋₆ alkyl or C₃₋₇ branched alkyl;R^(10b) is hydrogen, C₁₋₆ alkyl or C₃₋₇ branched alkyl;

R¹¹ is

R¹² is

each R^(13a) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇ branchedalkyl;each R^(13b) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇ branchedalkyl;each R^(14a) is independently hydrogen, C₁₋₆ alkyl, C₃₋₇ branched alkylor C(O)O-tert-butyl;each R^(14b) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇ branchedalkyl;X⁵ is N or CR^(7b);n1 is 1 or 2;n2 is 1 or 2;and m is 1, 2, 3, 4, 5, 6 or 7;each of X⁶, X^(6′) and X^(6″) is independently H, halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, orC₁₋₃(O)NR^(15a)R^(15b);each of X⁷ and X^(7′) is independently hydrogen, halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl orC₁₋₃(O)NR^(15a)R^(15b), or both X⁷ and X^(7′) together form C₃₋₆cycloalkyl or a heterocycle ring having 3-6 carbons and 0 or 1 oxygen,sulphur or nitrogen atoms in the ring, wherein each carbon ring atom ofthe C₃₋₆ cycloalkyl or the heterocycle is optionally substituted withhydrogen, C₁₋₃ alkyl, hydroxyl, halogen, amino, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ hydroxyalkyl or C₁₋₃(O)NR^(15a)R^(15b); when each of X⁶,X^(6′) and X^(6″) is hydrogen, at least X⁷ or X^(7′) is not hydrogen;when both X⁷ and X^(7′) are hydrogen, at least one of X⁶, X^(6′) andX^(6″) is not hydrogen;each of R^(15a) and R^(15b) is independently hydrogen, C₁₋₃ alkyl or C₃branched alkyl.

In some embodiments, the compounds have formula (II) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (II), or a complex thereof:

In some embodiments, the compounds have formula (III) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (III), or a complex thereof:

In some embodiments, the compounds have formula (IV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (IV), or a complex thereof:

In some embodiments, the compounds have formula (V) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (V), or a complex thereof:

wherein X⁸ is NH or O.

In some embodiments, the compounds have formula (VI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (VI), or a complex thereof:

wherein: one X⁸ is NH or O; and one X⁸ is CH₂.

In some embodiments, the compounds have formula (VII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (VII), or a complex thereof:

wherein: one X⁸ is NH or O; and each of two X⁸ is CH₂.

In some embodiments, the compounds have formula (VIII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (VIII), or a complex thereof:

In some embodiments, the compounds have formula (IX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (IX), or a complex thereof:

In some embodiments, the compounds have formula (X) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (X), or a complex thereof:

In some embodiments, the compounds have formula (XI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XI), or a complex thereof

In some embodiments, the compounds have formula (XII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XII), or a complex thereof

In some embodiments, the compounds have formula (XIII) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XIII), or a complex thereof

In some embodiments, the compounds have formula (XIV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XIV), or a complex thereof

In some embodiments, the compounds have formula (XV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XV), or a complex thereof:

In some embodiments, the compounds have formula (XVI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XVI), or a complex thereof:

The compounds of the present invention include compounds having formula(XVII) or an enantiomer, diastereomer, hydrate, solvate, orpharmaceutically acceptable salt of formula (XVII), or a complex thereof

In some embodiments, the compounds have formula (XVIII) or anenantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (XVIII), or a complex thereof:

In some embodiments, the compounds have formula (XIX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XIX), or a complex thereof:

In some embodiments, the compounds have formula (XX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XX), or a complex thereof:

In some embodiments, the compounds have formula (XXI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXI), or a complex thereof:

The compounds of the present invention include compounds having formula(XXII) or an enantiomer, diastereomer, hydrate, solvate, orpharmaceutically acceptable salt of formula (XXII), or a complexthereof:

In some embodiments, the compounds have formula (XXIII) or anenantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (XXIII), or a complex thereof:

In some embodiments, the compounds have formula (XXIV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXIV), or a complex thereof:

In some embodiments, the compounds have formula (XXV) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXV), or a complex thereof:

In some embodiments, the compounds have formula (XXVI) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXVI), or a complex thereof:

In some embodiments, the compounds have formula (XXVII) or anenantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (XXVII), or a complex thereof:

In some embodiments, the compounds have formula (XXVIII) or anenantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (XXVIII), or a complex thereof:

In some embodiments, the compounds have formula (XXIX) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (XXIX), or a complex thereof:

In some embodiments X¹ is O.

In some embodiments X¹ is S.

In some embodiments X¹ is SO.

In some embodiments X¹ is SO₂.

In some embodiments X² is O.

In some embodiments X² is S.

In some embodiments X² is SO.

In some embodiments X² is SO₂.

In some embodiments X³ is CH.

In some embodiments X³ is CF or N.

In some embodiments X³ is CF.

In some embodiments X³ is N.

In some embodiments X⁴ is CH.

In some embodiments X⁴ is N. In some embodiments only one X⁴ is N. Insome embodiments, two X⁴ is N. In some embodiments at least one X⁴ is Nand X³ is not N.

In some embodiments A is

In some embodiments A is

In some embodiments A is

In some embodiments R

In some embodiments R is

In some embodiments R

In some embodiments R is

In some embodiments R is

In some embodiments R¹ is

In some embodiments R¹ is hydrogen.

In some embodiments R¹ is C(O)O-tert-butyl.

In some embodiments R^(2a) is hydrogen.

In some embodiments R^(2a) is C₁₋₆ alkyl.

In some embodiments R^(2b) is hydrogen.

In some embodiments R^(2b) is C₁₋₆ alkyl.

In some embodiments R³ is hydrogen.

In some embodiments R³ is C₁₋₆ alkyl.

In some embodiments R³ is C₁₋₆ haloalkyl.

In some embodiments R³ is C(O)R⁹.

In some embodiments R³ is C(O)OR¹⁰.

In some embodiments R³ is not C(O)OR¹⁰.

In some embodiments R³ is C(O)NR^(10a)R^(10b).

In some embodiments R³ is CH₂C(O)OR^(10a).

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R⁴ is hydrogen.

In some embodiments R⁴ is C₁₋₆ alkyl.

In some embodiments R⁴ is C₁₋₆ haloalkyl.

In some embodiments R⁴ is C(O)R⁹.

In some embodiments R⁴ is C(O)OR¹⁰.

In some embodiments R⁴ is C(O)NR^(10a)R^(10b).

In some embodiments R⁴ is

In some embodiments R⁴ is

In some embodiments R⁴ is

In some embodiments R⁵ is hydrogen.

In some embodiments R⁵ is C₁₋₆ alkyl.

In some embodiments R⁵ is C₁₋₆ haloalkyl.

In some embodiments R⁵ is C(O)R⁹.

In some embodiments R⁵ is C(O)OR¹⁰.

In some embodiments R⁵ is C(O)NR^(10a)R^(10b).

In some embodiments R⁵ is

In some embodiments R⁵ is

In some embodiments R⁵ is

In some embodiments R⁶ is

In some embodiments R⁶ is NHR¹¹.

In some embodiments R⁶ is CH₂NHR¹².

In some embodiments R^(7a) is hydrogen.

In some embodiments R^(7a) is halogen. In some embodiments R^(7a) isfluorine.

In some embodiments R^(7a) is C₁₋₆ alkyl.

In some embodiments R^(7a) is C₃₋₇ branched alkyl.

In some embodiments R^(7a) is C₁₋₆ haloalkyl.

In some embodiments R^(7a) is C₁₋₆ alkoxy.

In some embodiments R^(7b) is hydrogen.

In some embodiments R^(7b) is halogen. In some embodiments R^(7b) isfluorine.

In some embodiments R^(7b) is C₁₋₆ alkyl.

In some embodiments R^(7b) is C₃₋₇ branched alkyl.

In some embodiments R^(7b) is C₁₋₆ haloalkyl.

In some embodiments R^(7b) is C₁₋₆ alkoxy.

In some embodiments R^(7c) is hydrogen.

In some embodiments R^(7c) is halogen. In some embodiments R^(7c) isfluorine.

In some embodiments R^(7c) is C₁₋₆ alkyl.

In some embodiments R^(7c) is C₃₋₇ branched alkyl.

In some embodiments R^(7c) is C₁₋₆ haloalkyl.

In some embodiments R^(7c) is C₁₋₆ alkoxy.

In some embodiments R⁸ is hydrogen.

In some embodiments R⁸ is halogen. In some embodiments R⁸ is fluorine.

In some embodiments R⁸ is C₁₋₆ alkyl.

In some embodiments R⁸ is C₃₋₇ branched alkyl

In some embodiments R⁸ is C₃₋₇ cycloalkyl.

In some embodiments R⁹ is C₁₋₆ alkyl.

In some embodiments R⁹ is C₃₋₇ branched alkyl.

In some embodiments R⁹ is

In some embodiments R¹⁰ is C₁₋₆ alkyl.

In some embodiments R¹⁰ is C₃₋₇ branched alkyl.

In some embodiments R^(10a) is hydrogen.

In some embodiments R^(10a) is C₁₋₆ alkyl.

In some embodiments R^(10a) is C₃₋₇ branched alkyl.

In some embodiments R^(10b) is hydrogen.

In some embodiments R^(10b) is C₁₋₆ alkyl.

In some embodiments R^(10b) is C₃₋₇ branched alkyl.

In some embodiments R¹¹ is

In some embodiments R¹¹ is

In some embodiments R¹² is

In some embodiments R¹² is

In some embodiments R^(13a) is hydrogen.

In some embodiments R^(13a) is C₁₋₆ alkyl.

In some embodiments R^(13a) is C₃₋₇ branched alkyl.

In some embodiments R^(13b) is hydrogen.

In some embodiments R^(13b) is C₁₋₆ alkyl.

In some embodiments R^(13b) is C₃₋₇ branched alkyl.

In some embodiments R^(14a) is hydrogen.

In some embodiments R^(14a) is C₁₋₆ alkyl.

In some embodiments R^(14a) is C₃₋₇ branched alkyl.

In some embodiments R^(14a) is C(O)O-tert-butyl.

In some embodiments R^(14b) is hydrogen.

In some embodiments R^(14b) is C₁₋₆ alkyl.

In some embodiments R^(14b) is C₃₋₇ branched alkyl.

In some embodiments X⁵ is N.

In some embodiments X⁵ is and CR^(7b).

In some embodiments n¹ is 1.

In some embodiments n¹ is 2.

In some embodiments n² is 1.

In some embodiments n² is 2.

In some embodiments m is 1.

In some embodiments m is 2.

In some embodiments m is 3.

In some embodiments m is 4.

In some embodiments m is 5.

In some embodiments m is 6.

In some embodiments m is 7.

In some embodiments X⁶ is halogen. The halogen may be chlorine. Thehalogen may be bromine. The halogen may be iodine. In some embodimentsX⁶ is fluorine.

In some embodiments X^(6′) is halogen. The halogen may be chlorine. Thehalogen may be bromine. The halogen may be iodine. In some embodimentsX^(6′) is fluorine.

In some embodiments X⁶″ is halogen. The halogen may be chlorine. Thehalogen may be bromine. The halogen may be iodine. In some embodimentsX⁶″ is fluorine.

In some embodiments X⁶ and X^(6′) are halogen. Each halogen mayindependently be chlorine, bromine, iodine or fluorine. In someembodiments X⁶ and X^(6′) are both fluorine.

In some embodiments X^(6′) and X⁶″ are halogen. Each halogen mayindependently be chlorine, bromine, iodine or fluorine. In someembodiments X^(6′) and X⁶″ are both fluorine.

In some embodiments X⁶ and X⁶″ are halogen. Each halogen mayindependently be chlorine, bromine, iodine or fluorine. In someembodiments X⁶ and X⁶″ are both fluorine.

In some embodiments X⁶, X^(6′) and X⁶″ are halogen. Each halogen mayindependently be chlorine, bromine, iodine or fluorine. In someembodiments each of X⁶, X^(6′) and X⁶″ is fluorine.

In some embodiments X⁶, X^(6′) and X⁶″ are halogen, H and H,respectively. In some embodiments X⁶, X^(6′) and X⁶″ are H, halogen andH, respectively. In some embodiments X⁶, X^(6′) and X⁶″ are H, H andhalogen, respectively. The halogen may be chlorine. The halogen may bebromine. The halogen may be iodine. In some embodiments X⁶, X^(6′) andX⁶″ are F, H and H, respectively. In some embodiments X⁶, X^(6′) and X⁶″are H, F and H, respectively. In some embodiments X⁶, X^(6′) and X⁶″ areH, H and F, respectively.

In some embodiments X⁶, X^(6′) and X⁶″ are each H.

In some embodiments X⁶ is C₁₋₃ alkyl. In some embodiments, X⁶ is methyl.

In some embodiments X⁶ is C₁₋₃ haloalkyl.

In some embodiments X⁶ is C₁₋₃ alkoxy.

In some embodiments X⁶ is C₁₋₃ hydroxyalkyl.

In some embodiments X⁶ is C₁₋₃(O)NR^(15a)R^(15b).

In some embodiments X^(6′) is C₁₋₃ alkyl. In some embodiments, X^(6′) ismethyl.

In some embodiments X^(6′) is C₁₋₃ haloalkyl.

In some embodiments X^(6′) is C₁₋₃ alkoxy.

In some embodiments X^(6′) is C₁₋₃ hydroxyalkyl.

In some embodiments X^(6′) is C₁₋₃(O)NR^(15a)R^(15b).

In some embodiments X^(6″) is C₁₋₃ alkyl. In some embodiments, X^(6″) ismethyl.

In some embodiments X^(6″) is C₁₋₃ haloalkyl.

In some embodiments X^(6″) is C₁₋₃ alkoxy.

In some embodiments X^(6″) is C₁₋₃ hydroxyalkyl.

In some embodiments X^(6″) is C₁₋₃(O)NR^(15a)R^(15b).

In some embodiments X⁷ is hydrogen.

In some embodiments X⁷ is halogen. The halogen may be chlorine. Thehalogen may be bromine. The halogen may be iodine. In some embodimentsX⁷ is fluorine.

In some embodiments X⁷ is C₁₋₃ alkyl. In some embodiments X⁷ is methyl.In some embodiments X⁷ is ethyl.

In some embodiments X⁷ is C₁₋₃ haloalkyl. In some embodiments, X⁷ isCH₂CF₃.

In some embodiments X⁷ is C₁₋₃ alkoxy.

In some embodiments X⁷ is C₁₋₃ hydroxyalkyl.

In some embodiments X⁷ is C₁₋₃ aminoalkyl.

In some embodiments X⁷ is C₁₋₃(O)NR^(15a)R^(15b).

In some embodiments X^(7′) is hydrogen.

In some embodiments X^(7′) is halogen. The halogen may be chlorine. Thehalogen may be bromine. The halogen may be iodine. In some embodimentsX^(7′) is fluorine.

In some embodiments X^(7′) is C₁₋₃ alkyl. In some embodiments X^(7′) ismethyl. In some embodiments X^(7′) is ethyl.

In some embodiments X^(7′) is C₁₋₃ haloalkyl. In some embodiments,X^(7′) is CH₂CF₃.

In some embodiments X^(7′) is C₁₋₃ alkoxy.

In some embodiments X^(7′) is C₁₋₃ hydroxyalkyl.

In some embodiments X^(7′) is C₁₋₃ aminoalkyl.

In some embodiments X^(7′) is C₁₋₃(O)NR^(15a)R^(15b).

In some embodiments both X⁷ and X^(7′) together form C₃₋₆ cycloalkylhaving 3-6 carbons. In some embodiments both X⁷ and X^(7′) together formC₃₋₆ heterocycle ring having 3-6 carbons and 1 oxygen, sulphur ornitrogen atom in the ring. In some embodiments both X⁷ and X^(7′)together form C₃₋₆ heterocycle ring having 3-6 carbons and 1 oxygen atomin the ring. In some embodiments both X⁷ and X^(7′) together form C₃₋₆heterocycle ring having 3-6 carbons and 1 sulphur atom in the ring. Insome embodiments both X⁷ and X^(7′) together form C₃₋₆ heterocycle ringhaving 3-6 carbons and 1 nitrogen atom in the ring. In some embodimentsno carbon ring atom of the C₃₋₆ cycloalkyl or the heterocycle issubstituted (except with hydrogen). In some embodiments, 1, 2 or 3 (or4, 5 or 6, if present) carbon ring atoms of the C₃₋₆ cycloalkyl or theheterocycle is substituted with C₁₋₃ alkyl, hydroxyl, halogen, amino,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl orC₁₋₃(O)NR^(15a)R^(15b). In some embodiments, the halogen is fluorine.

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

wherein R is H or C₁₋₃ alkyl.

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

wherein R is H or C₁₋₃ alkyl.

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

In some embodiments both X⁷ and X^(7′) together form

wherein R is H or C₁₋₃ alkyl.

In some embodiments both X⁷ and X^(7′) together form

In some embodiments R^(15a) is hydrogen.

In some embodiments R^(15a) is C₁₋₃ alkyl.

In some embodiments R^(15a) is C₃ branched alkyl.

In some embodiments R^(15b) is hydrogen.

In some embodiments R^(15b) is C₁₋₃ alkyl.

In some embodiments R^(15b) is C₃ branched alkyl.

In some embodiments, the compound excludes any compound having formula(Ia)

wherein:X⁶, X^(6′), X^(6″), X⁷ and X^(7′) are as defined for any embodimentsdefined above or elsewhere herein;R¹⁵ is: hydrogen; C₁-C₅ alkyl; halogen-substituted C₁-C₅ alkyl; acylselected from the group C₁-C₅ alkyl(C═O) and phenyl(C═O); substitutedheteroaryl representing a monocyclic aromatic group with two nitrogenatoms which is substituted by a halogen or (C₁-C₅) alkyl; (C₁-C₃)alkylsulphonyl; or phenylsulphonyl; andR^(16a), R^(16b), R^(16c) and R^(16d) are hydrogen or one or twosubstitutents simultaneously selected from the group consisting ofhalogen, (C₁-C₃) alkyl, halogen-substituted (C₁-C₃)alkyl,(C₁-C₃)alkylsulphonyl or cyano.

In some embodiments, the compounds have formula (XVIIIa) or anenantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (XVIIIa), or a complex thereof:

wherein one of X⁶, X^(6′) and X^(6″) is fluorine and two of X⁶, X^(6′)and X^(6″) are hydrogen. In some such embodiments, X⁶ is F. In some suchembodiments, X^(6′) is F. In some such embodiments, X^(6″) is F.

Exemplary embodiments include compounds having the formula (XXX) or anenantiomer, diastereomer, hydrate, solvate, prodrug, complex, orpharmaceutically acceptable salt form thereof:

wherein non-limiting examples of X¹, X², X³, X⁴, R^(2a), R^(2b) and R³are defined in Table 1A and for each of the 80 entries in Table 1A,non-limiting examples of X⁶, X^(6′), X^(6″), X⁷, X^(7′) are defined inTable 1B.

TABLE 1A Exemplary definitions for X¹, X², X³, X⁴, R^(2a), R^(2b) and R³in exemplary compounds of the formula (XXX) Entry X¹ X² X³ X⁴ R^(2a)R^(2b) R³ 1 SO₂ O N N H H

2 SO₂ O N N CH₃ H

3 SO₂ O N N CH₃ CH₃

4 O SO₂ N N CH₃ CH₃

5 O SO₂ N N H H

6 O SO₂ N N CH₃ H

7 SO₂ O CF N H H

8 SO₂ O CF N H CH₃

9 SO₂ O CF N CH₃ CH₃

10 O SO₂ CF N H H

11 O SO₂ CF CH H CH₃

12 O SO₂ CF CH CH₃ CH₃

13 SO₂ O N N H H

14 SO₂ O N N CH₃ H

15 SO₂ O N N CH₃ CH₃

16 SO₂ O CF N CH₃ CH₃

17 SO₂ O CF N H H

18 SO₂ O CF N H CH₃

19 SO₂ O CF H H H

20 SO₂ O CF N H H

21 SO₂ O N N CH₃ H

22 SO₂ O CF CH CH₃ CH₃

23 SO₂ O CF CH H H

24 SO₂ O CF CH H H

25 SO₂ O CF CH H H

26 SO₂ O CF CH H H

27 SO₂ O CF H H H

28 SO₂ O CF N H H

29 SO₂ O CF CH CH₃ CH₃

30 SO₂ O N N H H

31 SO₂ O CF CH CH₃ H

32 SO₂ O CF CH CH₃ CH₃

33 O SO₂ CF CH H H

34 O SO₂ CF CH CH₃ H

35 SO₂ O CF CH H H

36 O SO₂ CF CH H H

37 O SO₂ N N H H

38 O SO₂ CF CH CH₃ CH₃

39 O SO₂ CF CH H H

40 SO₂ O CF CH CH₃ H

41 S O N CH H H

42 S O CF CH CH₃ H

43 S O CF CH H CH₂CH₃

44 S O CF CH CH₃ CH₃

45 O S N CH H H

46 O S CF CH CH₃ H

47 O S CF CH H CH₂CH₃

48 O S CF CH CH₃ CH₃

49 SO O N CH H H

50 SO O CF CH CH₃ H

51 SO O CF CH H CH₂CH₃

52 SO O CF CH CH₃ CH₃

53 O SO N CH H H

54 O SO CF CH CH₃ H

55 O SO CF CH H CH₂CH₃

56 O SO CF CH CH₃ CH₃

57 S O N N H H

58 SO O N N H H

59 O S N N H H

60 O SO N N H H

61 SO O CF CH H H

62 SO O CF CH H H

63 SO O N CH H H

64 SO O CF CH H H

65 SO O CF CH H H

66 SO O CF CH H H

67 SO O CF CH H H

68 SO O N CH H H

69 SO O CF CH H H

70 SO O N N H H

71 SO O CF CH CH₃ H

72 SO O CF CH H CH₂CH₃

73 SO O CF CH CH₃ CH₃

74 O SO CF CH CH₃ CH₃

75 SO O CF CH H H

76 SO O CF CH H H

77 SO O CF CH H H

78 SO O CF CH H H

79 SO O CF CH H H

80 SO O CF CH H H

TABLE 1B Exemplary definitions for X⁶, X^(6′), X^(6″), X⁷ and X^(7′) inexemplary compounds of the formula (XXX) Entry X⁶ X^(6′) X^(6″) X⁷X^(7′) 1 H H H H F 2 H H H F H 3 H H H F F 4 H H F H H 5 H F H H H 6 F HH H H 7 H H H CH₃ CH₃ 8 H H F CH₃ CH₃ 9 H F H CH₃ CH₃ 10 F H H CH₃ CH₃11 H H H CH₂CH₃ CH₃ 12 H H F CH₂CH₃ CH₃ 13 H F H CH₂CH₃ CH₃ 14 F H HCH₂CH₃ CH₃ 15 H H H CH₃ CH₂CH₃ 16 H H F CH₃ CH₂CH₃ 17 H F H CH₃ CH₂CH₃18 F H H CH₃ CH₂CH₃ 19 H H H CH₂CH₃ CH₂CH₃ 20 H H F CH₂CH₃ CH₂CH₃ 21 H FH CH₂CH₃ CH₂CH₃ 22 F H H CH₂CH₃ CH₂CH₃ 23 H H H CH₂CF₃ CH₂CF₃ 24 H H HCH₂CF₃ CH₃ 25 H H H CH₂CF₃ CH₂CH₃ 26 H H H CH₃ CH₂CF₃ 27 H H H CH₂CH₃CH₂CF₃ 28 H H H

29 H H F

30 H F H

31 F H H

32 H H H

33 H H F

34 H F H

35 F H H

36 H H H

37 H H H

38 H H F

39 H F H

40 F H H

41 H H H

  where R is H or C₁₋₃ alkyl 42 H H F

  where R is H or C₁₋₃ alkyl 43 H F H

  where R is H or C₁₋₃ alkyl 44 F H H

  where R is H or C₁₋₃ alkyl 45 H H H

46 H H F

47 H F H

48 F H H

H H H

50 H H F

51 H F H

52 F H H

53 H H H

  where R is H or C₁₋₃ alkyl 54 H H F

  where R is H or C₁₋₃ alkyl 55 H F H

  where R is H or C₁₋₃ alkyl 56 F H H

  where R is H or C₁₋₃ alkyl 57 H H H

58 H H H

59 H H F

60 H F H

61 F H H

62 H H H

63 H H F

64 H F H

65 F H H

66 H H H

  where R is H or C₁₋₃ alkyl 67 H H F

  where R is H or C₁₋₃ alkyl 68 H F H

  where R is H or C₁₋₃ alkyl 69 F H H

  where R is H or C₁₋₃ alkyl 70 H H H

In some embodiments, the compound is a pharmaceutically acceptable saltof formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX),(XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX)or (XXX).

For the purposes of demonstrating the manner in which the compounds ofthe present disclosure are named and referred to herein, the compoundhaving the formula:

has the chemical name5-chloro-2-(4-{[4-(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine.

For the purposes of demonstrating the manner in which the compounds ofthe present disclosure are named and referred to herein, the compoundhaving the formula:

has the chemical name5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine.

For the purposes of demonstrating the manner in which the compounds ofthe present disclosure are named and referred to herein, the compoundhaving the formula:

has the chemical name5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine.

For the purposes of demonstrating the manner in which the compounds ofthe present disclosure are named and referred to herein, the compoundhaving the formula:

has the chemical name5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine.

For the purposes of the present disclosure, a compound depicted by theracemic formula, for example:

will stand equally well for either of the four stereoisomers having theformula

or the formula

or the formula

or the formula

or the formula

or the formula

or the formula

or the formula

or mixtures thereof, or in the case where more than one chiral center ispresent, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

It will also be appreciated by those of skilled in the art, may beadministered to a mammal and thereafter metabolized in the body to formcompounds of the invention which are pharmacologically active. Suchderivatives may therefore be described as “prodrugs”. All prodrugs ofcompounds of formula (I) are included within the scope of thisinvention.

It is understood that one skilled in the art would be able to makecompounds of the disclosure by similar methods as shown below, or bymethods known to one skilled in the art. It is also understood that oneskilled in the art would be able to make in a similar manner asdescribed below other compounds of formula (I) not specificallyillustrated below by using appropriate starting components and modifyingthe parameters of the synthesis as needed. In general, startingmaterials may be obtained from sources such as Sigma Aldrich, TCI andthe like, or synthesized according to sources known to those of skill inthe art (see Smith, M. B. and J. March, Advanced Organic Chemistry:Reactions, Mechanisms and Structure, 5^(th) edition (Wiley, December2000).

III. Combination Therapy

In another embodiment of the invention, a compound of the disclosure maybe combined with one or more additional compounds of the disclosure forthe treatment of tyrosine kinases-mediated disease and conditions. Thecompound of the disclosure may be administered simultaneously,sequentially or separately with the one or more additional compounds ofthe disclosure for the treatment of tyrosine kinases-mediated diseaseand conditions. In a further embodiment of the invention, a compound ofthe disclosure may be combined with one or more additional compounds ofthe disclosure and an excipient for the treatment of tyrosinekinases-mediated disease and conditions.

In another embodiment of the invention, a compound of the disclosure maybe combined with an anti-diabetic agent for the treatment of type 2diabetes mellitus-mediated disease and conditions. Said agents includebut not limited to metformin, sulfonylureas such as glimepiride,glyburide and glipizide. Glitazones such as pioglitazone androsiglitazone and glucagon-like peptide-1 (GLP-1) analogues and receptoragonists such as liraglutide, albiglutide, exenatide, exenatide-LAR, CJC1134, AVE 0010, R-51077, taspoglutide. DPP-4 inhibitors such assitagliptin, vildagliptin, linagliptin, saxagliptin, alogliptin, BI 1356BS, melogliptin, AMG 222, MP 513, PHX 1149, PSN 9301, R 1579, SYR 472,TA 6666, denagliptin GPR agonists such as TAK-875, AMG 837 and relatedFFAR1 agonists. Combination therapy also includes GPR119 agonists suchas APD668, APD597, BMS-903452, HD047703, GSK1292263 and MBX-2982. Thecompounds of the disclosure may be administered simultaneously,sequentially or separately with for the treatment of tyrosine-mediateddisease and conditions.

IV. Preparation of the Compounds of the Invention

The present invention further relates to a process for preparing thecompounds of the disclosure. Compounds of the present teachings can beprepared in accordance with the procedures outlined herein, fromcommercially available starting materials, compounds known in theliterature, or readily prepared intermediates, by employing standardsynthetic methods and procedures known to those skilled in the art.Standard synthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulations can bereadily obtained from the relevant scientific literature or fromstandard textbooks in the field. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions can vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures. Those skilled in the art oforganic synthesis will recognize that the nature and order of thesynthetic steps presented can be varied for the purpose of optimizingthe formation of the compounds described herein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of whichis incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

V. General Synthetic Schemes for Preparation of Compounds

Reagents used in the preparation of the compounds disclosed herein,including those of formulas (I) to (XXX), can be either commerciallyobtained or can be prepared by standard procedures described in theliterature. Compounds disclosed herein may be produced using one or moreof the following reaction schemes.

A compound of the formula (A-1), a known compound or compound preparedby known methods, is reacted with benzyl bromide in the presence of abase such as potassium carbonate, cesium carbonate, trimethylamine,pyridine, 2,6-lutidine, and the like, in a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, methylene chloride, N,N-dimethylformamideand the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (A-2). A compound offormula (A-2) is reacted with methylene bromide in the presence of abase such as potassium carbonate, cesium carbonate, trimethylamine,pyridine, 2,6-lutidine, and the like, in a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, methylene chloride, N,N-dimethylformamide,and the like, optionally in the presence of a crown ether such as18-crown-6, 12-crown-4, and the like optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (A-3). Acompound of formula (A-3) is oxidized with an oxidizing agent such ashydrogen peroxide in an acid such as acetic acid, formic acid,trifluoroacetic acid, and the like, optionally in the presence of asolvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide, and the like, optionally with heating, optionallywith microwave. The resulting material is reacted with hydrogen on acatalyst such as palladium on charcoal, palladium on carbon,tris(dibenzylideneacetone)dipalladium, palladium,tetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), raney nickel, and the like, ina solvent such as tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether,methanol, ethanol, and the like optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (A-4). Acompound of the formula (A-4) is reacted with trifluoromethanesulfonicanhydride in the presence of a base such as pyridine, 2,6-lutidine,2-picoline, 3-picoline, 4-picoline, N,N-dimethylaminopyridine,diisopropylethyl amine, trimethylamine and the like in a solvent such asmethylene chloride, 1,2-dichloroethane, chloroform, tetrahydrofuran,ether, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide and thelike optionally with heating, optionally with microwave irradiation toprovide compounds of the formula (A-5).

A compound of the formula (A-6), a known compound or compound preparedby known methods, is reacted with a sulfonyl chloride such asmethylsulfonyl chloride, toluene sulfonyl chloride, p-nitrophenylsulfonyl chloride in the presence of a base such as sodium carbonate,cesium carbonate, lithium carbonate, potassium carbonate, potassiumhydroxide, sodium hydroxide, lithium hydroxide, triethylamine,diisopropylethylamine and the like, in a solvent such as acetone,acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (A-7)wherein G1 is selected from the group consisting of methyl, tolyl andp-nitrophenyl. A compound of the formula (A-7), is reacted with acompound of the formula (A-8), a known compound prepared by knownmethods in the presence of a base such as sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, triethylamine,diisopropylethylamine and the like, in a solvent such asdimethylsulfoxide, N,N-dimethylformamide, acetone, acetonitrile,tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (A-9). A compound ofthe formula (A-9), is reacted with a4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane, a knowncompound prepared by known methods, in the presence of a base such aspotassium acetate, sodium carbonate, cesium carbonate, lithiumcarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide,lithium hydroxide, and the like in the presence of a palladium catalystsuch as palladium acetate, tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane,N,N-dimethylformamide, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (A-10).

A compound of the formula (A-10), is reacted with a compound of theformula (A-11), a known compound prepared by known methods in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-12).

A compound of the formula (A-12), is reacted with an acid such as formicacid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid,sulfuric acid and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methylene chloride, N,N-dimethylformamide,acetonitrile, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (A-13).

A compound of the formula (A-13), is reacted with an aldehyde in thepresence of a reducing agent such as sodium triacetoxyborohydride,lithium triacetoxyborohydride, sodium borohydride, lithium borohydride,and the like, optionally in the presence of an acid such as acetic acid,trifluoroacetic acid, hydrochloric acid, and the like, in the presenceof a solvent such as 1,4-dioxane, tetrahydrofuran,N,N-dimethylformamide, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (A-14).Alternatively, a compound of the formula (A-13), is reacted with aketone in the presence of a reducing agent such as sodiumtriacetoxyborohydride, lithium triacetoxyborohydride, sodiumborohydride, lithium borohydride, and the like, optionally in thepresence of an acid such as acetic acid, trifluoroacetic acid,hydrochloric acid, and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-14).

Alternatively, A compound of the formula (A-13), is reacted with acompound of the formula (A-15), a known compound or a compound preparedby known methods, in the presence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N-dicyclohexyl carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate, 1-hydroxy-7-azabenzotriazoleN-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the like, in thepresence of a base such as trimethylamine, pyridine, 2,6-lutidine,diisopropylethylamine, N-methylmorpholine, and the like in a solventsuch as acetonitrile, N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (A-16).

Alternatively, a compound of formula (A-13) is reacted with a compoundof the formula (A-17), a known compound or a compound prepared by knownmethods, in the presence of a base such as trimethylamine, pyridine,2,6-lutidine and the like, in a solvent such as acetonitrile,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-16).

A compound of the formula (A-13), is reacted withisocyanotrimethylsilane in the presence of a base such astrimethylamine, pyridine, 2,6-lutidine and the like, in a solvent suchas acetonitrile, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,and the like, optionally with heating, optionally, with microwaveirradiation to provide a compound of the formula (A-18).

A compound of the formula (A-13), is reacted with a compound of theformula (A-19) in the presence of a base such as trimethylamine,pyridine, 2,6-lutidine and the like in a solvent such as acetonitrile,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-20).

A compound of the formula (A-13), is reacted with a compound of theformula (A-21) in the presence of a base such as trimethylamine,pyridine, 2,6-lutidine and the like in a solvent such as acetonitrile,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and the likeoptionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-22).

A compound of the formula (A-13) is reacted with a compound of theformula (A-23), a known compound or a compound prepared by knownmethods, in the presence of sodium triacetoxyborohydride in the presenceof a solvent such as dichloromethane, dioxane, tetrahydrofuran, and thelike, optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-24). A compound of formula (A-24)is hydrolyzed in the presence of a base such as potassium hydroxide,sodium hydroxide, potassium carbonate, cesium carbonate, lithiumcarbonate optionally with heating, optionally with microwave irradiationto provide a compound of the formula (A-25).

A compound of formula (A-26) is reacted with trimethylsilyldiazomethanein hexanes in the presence of a base such as lithium diisopropylamide,sodium diisopropylamide, potassium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,and the like, optionally with cooling to −78° C. to provide a compoundof formula (A-27). A compound of formula (A-27) is reacted with areducing hydride reagent such as sodium borohydride, lithiumborohydride, lithium aluminum hydide, and the like, in a solvent such asmethanol, ethanol, 1,4-dioxane, tetrahydrofuran, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-28). A compound of formula (A-28)is reacted with a compound of formula (A-13) a known compound orcompound prepared by known methods, in the presence of a phosphine suchas triphenylphosphine, tri(o-tolyl)phosphine,resin-boundtriphenylphosphine, and the like, in the presence of an azodicarboxylatesuch as diethyl azodicarboxylate, diisopropyl azodicarboxylate,di-t-butylazodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, and thelike, in the presence of a solvent such as tetrahydrofuran, diethylether, 1,4-dioxane, methylene chloride, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-29).

A compound of formula (A-13) which is reacted with a compound of theformula (A-30), a known compound or a compound prepared by knownmethods, in the presence of a base such as potassium acetate, sodiumcarbonate, cesium carbonate, lithium carbonate, potassium carbonate,potassium hydroxide, sodium hydroxide, lithium hydroxide, in a solventsuch as acetonitrile, dimethylformamide, dioxane, tetrahydrofuran andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of the formula (A-31).

A compound of the formula (A-32), a known compound or compound preparedby known methods, is reacted with a compound of formula (A-33), in thepresence of a base such as sodium hydride, carbonate, cesium carbonate,lithium carbonate, potassium carbonate, triethylamine,diisopropylethylamine and the like, in a solvent such astetrahydrofuran, ethyl ether, acetonitrile acetonitrile,tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (A-34). A compound of the formula (A-34), is reacted with a4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane, in thepresence of abase such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II)dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike, in a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-35). A compound of the formula(A-35), is reacted with a compound of the formula (A-11), a knowncompound or a compound prepared by known methods, in the presence of abase such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-36). A compound of the formula(A-36), is reacted with an acid such as formic acid, trifluoroaceticacid, trichloroacetic acid, hydrochloric acid, sulfuric acid and thelike in the presence of a solvent such as 1,4-dioxane, tetrahydrofuran,methylene chloride, methanol, ethanol, and the like, optionally withheating, optionally with microwave irradiation. The resulting materialis reacted with a compound of the formula (A-37), a known compound or acompound prepared by known methods, in the presence of a base such astrimethylamine, pyridine, diisopropylethyl amine and the like, in asolvent such as acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-38).

A compound of the formula (A-39), a known compound or compound preparedby known methods, is reacted with a compound of formula (A-40), in thepresence of a base such as sodium hydride, carbonate, cesium carbonate,lithium carbonate, potassium carbonate, triethylamine,diisopropylethylamine and the like, in a solvent such astetrahydrofuran, ethyl ether, acetonitrile acetonitrile,tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (A-41). A compound of the formula (A-41), is reacted with asulfonyl chloride such as methylsulfonyl chloride, toluene sulfonylchloride, p-nitrophenyl sulfonyl chloride, and the like, in the presenceof a base such as sodium carbonate, cesium carbonate, lithium carbonate,potassium carbonate, potassium hydroxide, sodium hydroxide, lithiumhydroxide, triethylamine, diisopropylethylamine and the like in asolvent such as acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-42) wherein G¹ is selected from the group consisting ofmethyl, tolyl and p-nitrophenyl. A compound of the formula (A-42), isreacted with a compound of the formula (A-43), a known compound or acompound prepared by known methods, in the presence of a base such assodium carbonate, cesium carbonate, lithium carbonate, potassiumcarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide,triethylamine, diisopropylethylamine and the like, in a solvent such asacetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (A-44).A compound of the formula (A-44), is reacted with a4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-45). A compound of the formula(A-45), is reacted with a compound of the formula (A-11) in the presenceof a base such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II)dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike, in the presence of a solvent such as acetonitrile, acetone,tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (A-46).

A compound of formula (A-47), a known compound or a compound prepared byknown. methods is reacted with a base such potassium hydroxide, lithiumhydroxide, sodium hydroxide and the like, in the presence of a solventsuch as ethanol, methanol, isopropanol and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-48). A compound of formula (A-48), a known compound or acompound prepared by known methods is reacted with phosphoyl chloride ina base such pyridine, trimethylamine, 2,6-lutidine, picoline and thelike, optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-49).

A compound of formula (A-13) is reacted with a compound of the formula(A-49) in the presence of a base such as trimethylamine, pyridine,diisopropylethyl amine and the like, in a solvent such as acetonitrile,acetone, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (A-50).

A compound of formula (A-51), a known compound or a compound prepared byknown methods, is reacted with a compound of formula (A-52) in thepresence of a base such as trimethylamine, pyridine,diisopropylethylamine and the like, in a solvent such as toluene,benzene, and the like to provide a compound of formula (A-53). Acompound of formula (A-53) is reacted with a reducing agent such aslithium aluminum hydride, diisobutyl aluminum hydride, and the like, ina solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane and thelike, to provide a compound of formula (A-54). A compound of formula(A-54) is reacted with a compound of formula (A-55), a known compound ora compound prepared by known methods, in the presence of a phosphinesuch as triphenylphosphine, tri(o-tolyl)phosphine, resin-boundtriphenylphosphine, and the like, in the presence of an azodicarboxylatesuch as diethyl azodicarboxylate, diisopropyl azodicarboxylate ordi-t-butylazodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, and thelike, in the presence of a solvent such as tetrahydrofuran, diethylether, 1,4-dioxane and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (A-56).A compound of the formula (A-56), is reacted with an acid such as formicacid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid,sulfuric acid and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methanol, ethanol, methylene chloride, andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of formula (A-57). A compound of formula (A-57) isreacted with a compound of the formula (A-58), a known compound or acompound prepared by known methods, in the presence of a base such astrimethylamine, pyridine, diisopropylethyl amine and the like, in asolvent such as acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-59).

A compound of the formula (A-5), is reacted with a compound of theformula (A-60), a known compound prepared by known methods in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-61). A compound of the formula(A-61) is reacted with trifluoromethanesulfonic anhydride in thepresence of a base such as pyridine, 2,6-lutidine, 2-picoline,3-picoline, 4-picoline, N,N-dimethylaminopyridine, diisopropylethylamine, trimethylamine and the like in a solvent such as methylenechloride, 1,2-dichloroethane, chloroform, tetrahydrofuran, ether,1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide and the like,optionally with heating, optionally with microwave irradiation toprovide compounds of the formula (A-62). A compound of formula (A-62) isreacted with a compound of formula (A-63), a known compound or acompound prepared by known methods, in the presence of anorganophosphorus ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(R)-(+)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,[4(R)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[diphenylphosphine],(S)-(+)-5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,[4(S)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[diphenylphosphine],(R)-(+)-2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl,[(1R)-5,5′,6,6′,7,7′,8,8′-octahydro-[1,1′-binaphthalene]-2,2′-diyl]bis[diphenylphosphine],(S)-(+)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,[4(S)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[diphenylphosphine],(R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl, and the like, inthe presence of a palladium catalyst such as palladium acetate,palladium chloride, tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride, and the like, in asolvent such as toluene, benzene, xylene, tetrahydrofuran, 1,4-dioxane,acetonitrile, and the like, optionally in the presence of a base such astrimethylamine, pyridine, diisopropylethylamine and the like, optionallywith heating, optionally with microwave irradiation, to provide acompound of formula (A-64). A compound of the formula (A-64), is reactedwith an acid such as formic acid, trifluoroacetic acid, trichloroaceticacid, hydrochloric acid, sulfuric acid and the like in the presence of asolvent such as 1,4-dioxane, tetrahydrofuran, methanol, ethanol,methylene chloride, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of formula (A-65). Acompound of formula (A-65) is reacted with a compound of the formula(A-66) a known compound or a compound prepared by known methods, in thepresence of a base such as trimethylamine, pyridine, diisopropylethylamine and the like, in a solvent such as acetonitrile, acetone,tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (A-67).

A compound of the formula (A-5), a known compound or a compound preparedby known methods, is reacted with a compound of the formula (A-68), aknow compound or a compound prepared by known methods, in the presenceof a base such as potassium carbonate, sodium carbonate, potassiumhydroxide, sodium hydroxide, and the like, in the presence of apalladium catalyst such as 1,1′ (bisdiphenylphosphino)ferrocenedichloropalladium (II), tris(dibenzylideneacetone)dipalladium,palladium, tetrakis(triphenylphosphine), palladium acetate, palladiumchloride, (tridibenzylideneacetone) dipalladium(0), and the like, in thepresence of a solvent such as tetrahydrofuran, 1,4-dioxane, methylenechloride, acetonitrile, and the like, optionally in the presence ofwater, optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-69).

A compound of the formula (A-5), a known compound or a compound preparedby known methods, is reacted with a compound of the formula (A-70), aknow compound or a compound prepared by known methods, in the presenceof a base such as potassium carbonate, sodium carbonate, potassiumhydroxide, sodium hydroxide, and the like, in the presence of apalladium catalyst such as 1,1′ (bisdiphenylphosphino)ferrocenedichloropalladium (II), tris(dibenzylideneacetone)dipalladium,palladium, tetrakis(triphenylphosphine), palladium acetate, palladiumchloride, (tridibenzylideneacetone) dipalladium(0), and the like, in thepresence of a solvent such as tetrahydrofuran, 1,4-dioxane, methylenechloride, acetonitrile, and the like, optionally in the presence ofwater, optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-71).

A compound of the formula (A-72), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(A-73), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (A-74). A compound of the formula (A-74) is reacted with acompound of the formula (A-75) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-76). A compound of the formula(A-76) is reacted with a compound of the formula (A-5), known compoundor a compound prepared by known methods, in the presence of a base suchas potassium carbonate, sodium carbonate, potassium hydroxide, sodiumhydroxide, and the like, in the presence of a palladium catalyst such as1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-77). A compound of the formula(A-77) is then reacted with an acid such as hydrochloric acid,hydrobromic acid, trifluoroacetic acid, acetic acid, formic acid, andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of the formula (A-78). A compound of the formula(A-78) is reacted with an aldehyde in the presence of a reducing agentsuch as sodium triacetoxy borohydride, sodium borohydride, and the like,optionally in the presence of an acid such as acetic acid, formic acid,hydrochloric acid, and the like, in a solvent such as tetrahydrofuran,1,4-dioxane, methylene chloride, methanol, ethanol, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-79). Alternatively, a compound ofthe formula (A-78) is reacted with a ketone in the presence of areducing agent such as sodium triacetoxy borohydride, sodiumborohydride, and the like, optionally in the presence of an acid such asacetic acid, formic acid, hydrochloric acid, and the like, in a solventsuch as tetrahydrofuran, 1,4-dioxane, methylene chloride, methanol,ethanol, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (A-79).

A compound of the formula (A-80), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(A-81), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (A-82). A compound of the formula (A-82) is reacted with acompound of the formula (A-83) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-84). A compound of the formula(A-84) is reacted with a compound of the formula (A-85), known compoundor a compound prepared by known methods, in the presence of a base suchas potassium carbonate, sodium carbonate, potassium hydroxide, sodiumhydroxide, and the like, in the presence of a palladium catalyst such as1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-86).

A compound of the formula (A-87), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(A-88), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (A-89). A compound of the formula (A-89) is reacted with acompound of the formula (A-90) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-91). A compound of the formula(A-91) is reacted with a compound of the formula (A-92), known compoundor a compound prepared by known methods, in the presence of a base suchas potassium carbonate, sodium carbonate, potassium hydroxide, sodiumhydroxide, and the like, in the presence of a palladium catalyst such as1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-93).

A compound of the formula (A-94), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(A-95), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (A-96). A compound of the formula (A-96) is reacted with acompound of the formula (A-97) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-98). A compound of the formula(A-98) is reacted with a compound of the formula (A-99), known compoundor a compound prepared by known methods, in the presence of a base suchas potassium carbonate, sodium carbonate, potassium hydroxide, sodiumhydroxide, and the like, in the presence of a palladium catalyst such as1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-100).

A compound of the formula (A-101), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(A-102), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (A-103). A compound of the formula (A-103) is reacted with acompound of the formula (A-104) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-105). A compound of the formula(A-105) is reacted with a compound of the formula (A-106), knowncompound or a compound prepared by known methods, in the presence of abase such as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, and the like, in the presence of a palladium catalystsuch as 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-107).

A compound of the formula (A-108) is reacted with a compound of theformula (A-109), a known compound or a compounds prepared by knownmethods, in the presence of a base such as triethylamine,diisopropylethyl amine, pyridine, 2,6-lutidine, and the like, in thepresence of a solvent such as acetonitrile, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-110).

A compound of the formula (A-111) is reacted with hydrogen in thepresence of a palladium catalyst such as palladium on carbon,tris(dibenzylideneacetone)dipalladium, palladium,tetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methanol, ethanol,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (A-112).

A compound of the formula (A-113) is reacted with a compound of theformula (A-114), a known compound or a compounds prepared by knownmethods, in the presence of a base such as triethylamine,diisopropylethyl amine, pyridine, 2,6-lutidine, and the like, in thepresence of a solvent such as acetonitrile, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-115).

A compound of the formula (A-116) is reacted with hydrogen in thepresence of a palladium catalyst such as palladium on carbon,tris(dibenzylideneacetone)dipalladium, palladium,tetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methanol, ethanol,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (A-117).

A compound of formula (A-118) is reacted with trimethylsilyldiazomethanein hexanes in the presence of a base such as lithium diisopropylamide,sodium diisopropylamide, potassium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,and the like, optionally with cooling to −78° C. to provide a compoundof formula (A-119). A compound of formula (A-119) is reacted with areducing hydride reagent such as sodium borohydride, lithiumborohydride, lithium aluminum hydide, and the like, in a solvent such asmethanol, ethanol, 1,4-dioxane, tetrahydrofuran, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (A-120). A compound of formula (A-120)is reacted with a compound of formula (A-121) a known compound orcompound prepared by known methods, in the presence of a phosphine suchas triphenylphosphine, tri(o-tolyl)phosphine,resin-boundtriphenylphosphine, and the like, in the presence of an azodicarboxylatesuch as diethyl azodicarboxylate, diisopropyl azodicarboxylate,di-t-butylazodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, and thelike, in the presence of a solvent such as tetrahydrofuran, diethylether, 1,4-dioxane, methylene chloride, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (A-122).

A compound of the formula (B-1), a known compound or compound preparedby known methods, is reacted with a compound of the formula (B-2)wherein M is a metal such as sodium, lithium, potassium, and the like,in a solvent such as methanol, ethanol, isopropanol, t-butanol,neopentanol, tetrahydrofuran, 1,4-dioxane, methylene chloride. and thelike, optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-3).

A compound of the formula (B-4), a known compound or compound preparedby known methods, is reacted with a compound of the formula (B-3), inthe presence of a Lewis acid such as boron trifluoride etherate, borontrichloride, trimethyl borate, triethyl borate, aluminum chloride, ironchloride, magnesium chloride, chromium chloride, titaniumtetramethoxide, titanium tetraethoxide, tin chloride, cobalt chlorideand the like, in the presence of a solvent such as methylene chloride,tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like,optionally with heating, optionally with microwave irradiation to give acompound of formula (B-5). The compound of formula (B-5) is reacted witha base such as sodium carbonate, cesium carbonate, lithium carbonate,potassium carbonate, potassium hydroxide, sodium hydroxide, lithiumhydroxide, and the like in a solvent such as, methylene chloride,acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally in the presence of a crownether such as 18-crown-6, 12-crown-4, 15-crown-5, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-6).

A compound of the formula (B-6) is reacted with an oxidizing agent suchas m-chloroperoxybenzoic acid, monoperphthalic acid, peracetic acid,perpropionic acid, pertrifluoroacetic acid, potassium periodate, sodiummetaperiodate, sodium perborate, potassium peroxymonosulfate (Oxone®),potassium peroxydisulfate, dimethyldioxirane, and the like, in thepresence of a solvent such as tetrahydrofuran, ether, 1,4-dioxane,acetone, acetonitrile, methanol, ethanol, isopropanol, water, optionallywith heating, optionally with microwave irradiation to provide compoundsof the formula (B-7). Alternatively, a compound of the formula (B-6) isreacted with a sulfoxide such as diphenyl sulfoxide, dimethyl sulfoxide,and the like, in the presence of a rhenium catalyst such asReOCl₃(PPh₃)₂, and the like, in a solvent such as methylene chloride,1,2-dichloroethane, chloroform, tetrahydrofuran, ether, 1,4-dioxane,acetone, acetonitrile, and the like, optionally with heating, optionallywith microwave irradiation to provide compounds of the formula (B-7).Alternatively, a compound of the formula (B-6) is reacted with ureahydrogen peroxide complex in the presence of a rhenium catalyst such asReOCl₃(PPh₃)₂, and the like, in a solvent such as methylene chloride,1,2-dichloroethane, chloroform, tetrahydrofuran, ether, 1,4-dioxane,acetone, acetonitrile, N,N-dimethylformamide, optionally with heating,optionally with microwave irradiation to provide compounds of theformula (B-7). Alternatively, a compound of the formula (B-6) is reactedwith hydrogen peroxide in the presence titanium (IV)isopropoxide-diethyltartarate, optionally in the presence of an aminoalcohol such as 2-amino-3-phenylpropan-1-ol,2-amino-4-methylpentan-1-ol, 2-amino-4-(methylthio)butan-1-ol,2-aminopropan-1-ol, and the like, in a solvent such as methylenechloride, 1,2-dichloroethane, chloroform, tetrahydrofuran, ether,1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide optionallywith heating, optionally with microwave irradiation to provide compoundsof the formula (B-7). Alternatively, a compound of the formula (B-6) isreacted with an oxidoreductase such as Baeyer-Villiger monooxygenase,cytochrome P450 2C9, cytochrome P450 2C19, cytochrome P450 3A4 and, in asolvent such as water, methanol, ethanol, isopropanol, acetonitrile,acetone, and the like, optionally with heating, optionally withmicrowave irradiation to provide compounds of the formula (B-7).Alternatively, a compound of the formula (B-6) is electrochemicallyoxidized optionally in the presence of a buffer solution such as asodium phosphate solution, a potassium phosphate solution, and the liketo provide compounds of the formula (B-7). Alternatively, a compound ofthe formula (B-6) is photochemically oxidized in a solvent such asmethylene chloride, 1,2-dichloroethane, chloroform, tetrahydrofuran,ether, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide, water,methanol, ethanol, isopropanol, and the like, optionally with heating,optionally with microwave irradiation to provide compounds of theformula (B-7). The compound of formula (B-7) is reacted with an acidsuch as trifluoacetic acid, hydrochloric acid, sulfuric acid, hydrogenbromide, and the like in a solvent such as, methylene bromide, acetone,acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-8). Acompound of formula (B-8) is reacted with a sulfonyl anhydride such asmethylsulfonyl anhydride, trifluoromethanesulfonic anhydride, and thelike, in the presence of a base such as pyridine, 2,6-lutidine,2-picoline, 3-picoline, 4-picoline, N,N-dimethylaminopyridine,diisopropylethyl amine, trimethylamine and the like in a solvent such asmethylene chloride, 1,2-dichloroethane, chloroform, tetrahydrofuran,ether, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide and thelike optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-9) wherein G¹ is selected from thegroup consisting of methyl and trifluoromethyl.

Alternatively, a compound of the formula (B-6) is reacted with an acidsuch as trifluoacetic acid, hydrochloric acid, sulfuric acid, hydrogenbromide, and the like in a solvent such as, methylene bromide, acetone,acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-8a).A compound of the formula (B-8a) is reacted with a sulfonyl anhydridesuch as methylsulfonyl anhydride, trifluoromethanesulfonic anhydride,and the like, in the presence of a base such as pyridine, 2,6-lutidine,2-picoline, 3-picoline, 4-picoline, N,N-dimethylaminopyridine,diisopropylethyl amine, trimethylamine and the like in a solvent such asmethylene chloride, 1,2-dichloroethane, chloroform, tetrahydrofuran,ether, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide and thelike optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-9a) wherein G¹ is selected from thegroup consisting of methyl and trifluoromethyl.

A compound of the formula (B-10), a known compound or compound preparedby known methods, is reacted with a compound of the formula (B-11), aknown compound or a compound prepared by known methods wherein G² isselected from the group consisting of methyl, trifluoromethyl, tolyl,and p-nitrophenyl, in the presence of a base such as sodium carbonate,cesium carbonate, lithium carbonate, potassium carbonate, potassiumhydroxide, sodium hydroxide, lithium hydroxide, triethylamine,diisopropylethylamine and the like in a solvent such as acetone,acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-12).A compound of the formula (B-12), is reacted with a compound of theformula (B-13), a known compound prepared by known methods in thepresence of a base such as sodium carbonate, cesium carbonate, lithiumcarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide,lithium hydroxide, triethylamine, diisopropylethylamine and the like, ina solvent such as acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, dimethylsulfoxide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-14). A compound of the formula(B-14), is reacted with a compound of the formula (B-15) in the presenceof a base such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, potassium tert-butoxide, sodiumtert-butoxide, lithium tert-butoxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike, in a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-16).

A compound of the formula (B-17), is reacted with a compound of theformula (B-18), a known compound prepared by known methods in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodiumtert-butoxide, lithium tert-butoxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-19).

A compound of the formula (B-20), is reacted with an acid such as formicacid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid,sulfuric acid and the like, optionally in a solvent such as methanol,ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane and the like,optionally with heating, optionally with microwave irradiation, to givea compound of the formula (B-21). A compound of the formula (B-21) isreacted with a compound of the formula (B-22), a known compound or acompound prepared by known methods, in the presence of a base such aspotassium acetate, sodium carbonate, cesium carbonate, lithiumcarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide,lithium hydroxide, triethylamine, diisopropyethyl amine, and the like,in a solvent such as acetonitrile, N, N-dimethylformamide, 1,4-dioxane,tetrahydrofuran and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (B-23).

A compound of the formula (B-20a), is reacted with an acid such asformic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloricacid, sulfuric acid and the like, optionally in a solvent such asmethanol, ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane andthe like, optionally with heating, optionally with microwaveirradiation, to give a compound of the formula (B-21a). A compound ofthe formula (B-21a) is reacted with a compound of the formula (B-22a), aknown compound or a compound prepared by known methods, in the presenceof a base such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, triethylamine, diisopropyethyl amine, andthe like, in a solvent such as acetonitrile, N,N-dimethylformamide,1,4-dioxane, tetrahydrofuran and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-23a).

A compound of the formula (B-24), is reacted with an acid such as formicacid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid,sulfuric acid and the like, optionally in a solvent such as methanol,ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane and the like,optionally with heating, optionally with microwave irradiation, to givea compound of the formula (B-25). A compound of the formula (B-25) isreacted with a compound of the formula (B-26), a known compound or acompound prepared by known methods, in the presence of abase such aspotassium acetate, sodium carbonate, cesium carbonate, lithiumcarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide,lithium hydroxide, triethylamine, diisopropyethyl amine, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-27). A compound of the formula(B-27), is reacted with a compound of the formula (B-28) in the presenceof a base such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, potassium tert-butoxide, sodiumtert-butoxide, lithium tert-butoxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-29).

A compound of the formula (B-24a), is reacted with an acid such asformic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloricacid, sulfuric acid and the like, optionally in a solvent such asmethanol, ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane andthe like, optionally with heating, optionally with microwaveirradiation, to give a compound of the formula (B-25a). A compound ofthe formula (B-25a) is reacted with a compound of the formula (B-26a), aknown compound or a compound prepared by known methods, in the presenceof a base such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, triethylamine, diisopropyethyl amine, andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of the formula (B-27a). A compound of the formula(B-27a), is reacted with a compound of the formula (B-28a) in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodiumtert-butoxide, lithium tert-butoxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-29a).

A compound of the formula (B-30), is reacted with a compound of theformula (B-31), a known compound prepared by known methods wherein G¹ isselected from the group consisting of methyl and trifluoromethyl, in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-32).

A compound of the formula (B-30), is reacted with a compound of theformula (B-31), a known compound prepared by known methods wherein G¹ isselected from the group consisting of methyl and trifluoromethyl, in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-32).

A compound of the formula (B-33), a known compound or compound preparedby known methods, is reacted with with trifluoromethanesulfonicanhydride in the presence of a base such as pyridine, 2,6-lutidine,2-picoline, 3-picoline, 4-picoline, N,N-dimethylaminopyridine,diisopropylethyl amine, trimethylamine and the like, in a solvent suchas methylene chloride, 1,2-dichloroethane, chloroform, tetrahydrofuran,ether, 1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide and thelike, optionally with heating, optionally with microwave irradiation toprovide compounds of the formula (B-34). A compound of formula (B-34) isreacted with methylene bromide in the presence of a base such aspotassium carbonate, cesium carbonate, trimethylamine, pyridine, and thelike, in a solvent such as acetonitrile, methylene chloride,N,N-dimethylformamide, and the like, optionally in the presence of acrown ether such as 18-crown-6, 12-crown-4, and the like, optionallywith heating, optionally with microwave irradiation to provide acompound of the formula (B-35). A compound of formula (B-35) is oxidizedwith an oxidizing agent such as m-chlorobenzoic acid, hydrogen peroxidein an acid such as acetic acid, formic acid, trifluoroacetic acid, andthe like, optionally in the presence of a solvent such as methanol,ethanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and thelike, optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-36).

A compound of the formula (B-37), a known compound or compound preparedby known methods, is reacted with a sulfonyl chloride such asmethylsulfonyl chloride, toluene sulfonyl chloride, p-nitrophenylsulfonyl chloride in the presence of a base such as sodium carbonate,cesium carbonate, lithium carbonate, potassium carbonate, potassiumhydroxide, sodium hydroxide, lithium hydroxide, triethylamine,diisopropylethylamine and the like, in a solvent such as acetone,acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-38)wherein G³ is selected from the group consisting of methyl, tolyl andp-nitrophenyl. A compound of the formula (B-38), is reacted with acompound of the formula (B-39), a known compound prepared by knownmethods in the presence of a base such as sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, triethylamine,diisopropylethylamine and the like, in a solvent such asdimethylsulfoxide, N, N-dimethylformamide, acetone, acetonitrile,tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (B-40). A compound ofthe formula (B-40), is reacted with a4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane, a knowncompound prepared by known methods, in the presence of a base such aspotassium acetate, sodium carbonate, cesium carbonate, lithiumcarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide,lithium hydroxide, and the like in the presence of a palladium catalystsuch as palladium acetate, tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-41).

A compound of the formula (B-41), is reacted with a compound of theformula (B-42), a known compound prepared by known methods in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-43).

A compound of the formula (B-43), is reacted with an acid such as formicacid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid,sulfuric acid and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methylene chloride, N,N-dimethylformamide,acetonitrile, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (B-44).

A compound of the formula (B-44), is reacted with an aldehyde in thepresence of a reducing agent such as sodium triacetoxyborohydride,lithium triacetoxyborohydride, sodium borohydride, lithium borohydride,and the like, optionally in the presence of an acid such as acetic acid,trifluoroacetic acid, hydrochloric acid, and the like, in the presenceof a solvent such as 1,4-dioxane, tetrahydrofuran,N,N-dimethylformamide, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-45).Alternatively, a compound of the formula (B-44), is reacted with anketone in the presence of a reducing agent such as sodiumtriacetoxyborohydride, lithium triacetoxyborohydride, sodiumborohydride, lithium borohydride, and the like, optionally in thepresence of an acid such as acetic acid, trifluoroacetic acid,hydrochloric acid, and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-45).

Alternatively, A compound of the formula (B-44), is reacted with acompound of the formula (B-46), a known compound or a compound preparedby known methods, in the presence of a coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,N,N′-dicyclohexyl carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide,hexafluorophosphate, 1-hydroxy-7-azabenzotriazole,N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminiumhexafluorophosphate,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide andthe like, in the presence of a base such as trimethylamine, pyridine,2,6-lutidine, diisopropylethylamine, N-methylmorpholine, and the like ina solvent such as acetonitrile, N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (B-47).

Alternatively, a compound of formula (B-44) is reacted with a compoundof the formula (B-48), a known compound or a compound prepared by knownmethods, in the presence of a base such as trimethylamine, pyridine,2,6-lutidine and the like, in a solvent such as acetonitrile,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-49).

A compound of the formula (B-44), is reacted with a reagent of theformula (B-50) in the presence of a base such as trimethylamine,pyridine, 2,6-lutidine and the like, in a solvent such as acetonitrile,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran optionally withheating, optionally, with microwave irradiation to provide a compound ofthe formula (B-51).

A compound of the formula (B-44), is reacted with a compound of theformula (B-52) in the presence of a base such as trimethylamine,pyridine, 2,6-lutidine and the like in a solvent such as acetonitrile,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-53).

A compound of the formula (B-44), is reacted with a compound of theformula (B-54) in the presence of a base such as trimethylamine,pyridine, 2,6-lutidine and the like in a solvent such as acetonitrile,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-55).

A compound of formula (B-56) is reacted with trimethylsilyldiazomethanein hexanes in the presence of a base such as lithium diisopropylamide,sodium diisopropylamide, potassium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,and the like, optionally with cooling to −78° C. to provide a compoundof formula (B-57). A compound of formula (B-57) is reacted with areducing hydride reagent such as sodium borohydride, lithiumborohydride, lithium aluminum hydide, and the like, in a solvent such asmethanol, ethanol, 1,4-dioxane, tetrahydrofuran, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-58). A compound of formula (B-58)is reacted with a compound of formula (B-59) a known compound orcompound prepared by known methods, in the presence of a phosphine suchas triphenylphosphine, tri(o-tolyl)phosphine,resin-boundtriphenylphosphine, and the like, in the presence of an azodicarboxylatesuch as diethyl azodicarboxylate, diisopropyl azodicarboxylate,di-t-butylazodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, and thelike, in the presence of a solvent such as tetrahydrofuran, diethylether, 1,4-dioxane, methylene chloride, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-60).

A compound of formula (B-44) which is reacted with a compound of theformula (B-61), a known compound or a compound prepared by knownmethods, in the presence of a base such as potassium acetate, sodiumcarbonate, cesium carbonate, lithium carbonate, potassium carbonate,potassium hydroxide, sodium hydroxide, lithium hydroxide, in a solventsuch as acetonitrile, dimethylformamide, dioxane, tetrahydrofuran andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of the formula (B-62).

A compound of the formula (B-63), a known compound or compound preparedby known methods, is reacted with a compound of formula (B-64), in thepresence of a base such as sodium hydride, carbonate, cesium carbonate,lithium carbonate, potassium carbonate, triethylamine,diisopropylethylamine and the like, in a solvent such astetrahydrofuran, ethyl ether, acetonitrile acetonitrile,tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-65). A compound of the formula (B-65), is reacted with a4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane, in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike, in a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-66). A compound of the formula(B-66), is reacted with a compound of the formula (B-67), a knowncompound or a compound prepared by known methods, in the presence of abase such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-68). A compound of the formula(B-68), is reacted with an acid such as formic acid, trifluoroaceticacid, trichloroacetic acid, hydrochloric acid, sulfuric acid and thelike in the presence of a solvent such as 1,4-dioxane, tetrahydrofuran,methylene chloride, methanol, ethanol, and the like, optionally withheating, optionally with microwave irradiation. The resulting materialis reacted with a compound of the formula (B-69), a known compound or acompound prepared by known methods, in the presence of a base such astrimethylamine, pyridine, diisopropylethyl amine and the like, in asolvent such as acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-70).

A compound of the formula (B-71), a known compound or compound preparedby known methods, is reacted with a compound of formula (B-72), in thepresence of a base such as sodium hydride, carbonate, cesium carbonate,lithium carbonate, potassium carbonate, triethylamine,diisopropylethylamine and the like, in a solvent such astetrahydrofuran, ethyl ether, acetonitrile acetonitrile,tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-73). A compound of the formula (B-73), is reacted with asulfonyl chloride such as methylsulfonyl chloride, toluene sulfonylchloride, p-nitrophenyl sulfonyl chloride, and the like, in the presenceof a base such as sodium carbonate, cesium carbonate, lithium carbonate,potassium carbonate, potassium hydroxide, sodium hydroxide, lithiumhydroxide, triethylamine, diisopropylethylamine and the like in asolvent such as acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-74) wherein G⁵ is selected from the group consisting ofmethyl, tolyl and p-nitrophenyl. A compound of the formula (B-74), isreacted with a compound of the formula (B-75), a known compound or acompound prepared by known methods, in the presence of a base such assodium carbonate, cesium carbonate, lithium carbonate, potassiumcarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide,triethylamine, diisopropylethylamine and the like, in a solvent such asacetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-76).A compound of the formula (B-76), is reacted with a4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolanein thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-77). A compound of the formula(B-77), is reacted with a compound of the formula (B-78) in the presenceof a base such as potassium acetate, sodium carbonate, cesium carbonate,lithium carbonate, potassium carbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, and the like, in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike, in the presence of a solvent such as acetonitrile, acetone,tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (B-79).

A compound of formula (B-80), a known compound or a compound prepared byknown. methods is reacted with a base such potassium hydroxide, lithiumhydroxide, sodium hydroxide and the like, in the presence of a solventsuch as ethanol, methanol, isopropanol and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-81). A compound of formula (B-81), a known compound or acompound prepared by known methods is reacted with phosphoyl chloride ina base such pyridine, trimethylamine, 2,6-lutidine, picoline and thelike, optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-82).

A compound of formula (B-83) is reacted with a compound of the formula(B-82) in the presence of a base such as trimethylamine, pyridine,diisopropylethyl amine and the like, in a solvent such as acetonitrile,acetone, tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-84).

A compound of formula (B-85), a known compound or a compound prepared byknown methods, is reacted with a compound of formula (B-86) in thepresence of a base such as trimethylamine, pyridine,diisopropylethylamine and the like, in a solvent such as toluene,benzene, and the like to provide a compound of formula (B-87). Acompound of formula (B-87) is reacted with a reducing agent such aslithium aluminum hydride, diisobutyl aluminum hydride, and the like, ina solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane and thelike, to provide a compound of formula (B-88). A compound of formula(B-88) is reacted with a compound of formula (B-89), a known compound ora compound prepared by known methods, in the presence of a phosphinesuch as triphenylphosphine, tri(o-tolyl)phosphine, resin-boundtriphenylphosphine, and the like, in the presence of an azodicarboxylatesuch as diethyl azodicarboxylate, diisopropyl azodicarboxylate ordi-t-butylazodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, and thelike, in the presence of a solvent such as tetrahydrofuran, diethylether, 1,4-dioxane and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of the formula (B-90).A compound of the formula (B-90), is reacted with an acid such as formicacid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid,sulfuric acid and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methanol, ethanol, methylene chloride, andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of formula (B-91). A compound of formula (B-91) isreacted with a compound of the formula (B-92), a known compound or acompound prepared by known methods, in the presence of a base such astrimethylamine, pyridine, diisopropylethyl amine and the like, in asolvent such as acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-93).

A compound of the formula (B-94), is reacted with a compound of theformula (B-95), a known compound prepared by known methods in thepresence of a base such as potassium acetate, sodium carbonate, cesiumcarbonate, lithium carbonate, potassium carbonate, potassium hydroxide,sodium hydroxide, lithium hydroxide, and the like in the presence of apalladium catalyst such as palladium acetate,tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike a solvent such as acetonitrile, acetone, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-96). A compound of the formula(B-96) is reacted with trifluoromethanesulfonic anhydride in thepresence of a base such as pyridine, 2,6-lutidine, 2-picoline,3-picoline, 4-picoline, N,N-dimethylaminopyridine, diisopropylethylamine, trimethylamine and the like in a solvent such as methylenechloride, 1,2-dichloroethane, chloroform, tetrahydrofuran, ether,1,4-dioxane, acetone, acetonitrile, N,N-dimethylformamide and the like,optionally with heating, optionally with microwave irradiation toprovide compounds of the formula (B-97). A compound of formula (B-97) isreacted with a compound of formula (B-98), a known compound or acompound prepared by known methods, in the presence of anorganophosphorus ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,(R)-(+)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,[4(R)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[diphenylphosphine],(S)-(+)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,[4(S)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[diphenylphosphine],(R)-(+)-2,2′-Bis(diphenylphospino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl,[(1R)-5,5′,6,6′,7,7′,8,8′-octahydro-[1,1′-binaphthalene]-2,2′-diyl]bis[diphenylphosphine],(S)-(+)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,[4(S)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[diphenylphosphine],(R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,(S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl, and the like, inthe presence of a palladium catalyst such as palladium acetate,palladium chloride, tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride, and the like, in asolvent such as toluene, benzene, xylene, tetrahydrofuran, 1,4-dioxane,acetonitrile, and the like, optionally in the presence of a base such astrimethylamine, pyridine, diisopropylethylamine and the like, optionallywith heating, optionally with microwave irradiation, to provide acompound of formula (B-99). A compound of the formula (B-99), is reactedwith an acid such as formic acid, trifluoroacetic acid, trichloroaceticacid, hydrochloric acid, sulfuric acid and the like in the presence of asolvent such as 1,4-dioxane, tetrahydrofuran, methanol, ethanol,methylene chloride, and the like, optionally with heating, optionallywith microwave irradiation to provide a compound of formula (B-100). Acompound of formula (B-100) is reacted with a compound of the formula(B-101) a known compound or a compound prepared by known methods, in thepresence of a base such as trimethylamine, pyridine, diisopropylethylamine and the like, in a solvent such as acetonitrile, acetone,tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (B-102).

A compound of the formula (B-103), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(B-104), a know compound or a compound prepared by known methods, in thepresence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in the presence ofa palladium catalyst such as1,1′(bisdiphenylphosphino)ferrocenedichloropalladium(II),tris(dibenzylideneacetone)dipalladium, palladium,tetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-105).

A compound of the formula (B-106), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(B-107), a know compound or a compound prepared by known methods, in thepresence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in the presence ofa palladium catalyst such as1,1′(bisdiphenylphosphino)ferrocenedichloropalladium(II),tris(dibenzylideneacetone)dipalladium, palladium,tetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-108).

A compound of the formula (B-109), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(B-110), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-111). A compound of the formula (B-111) is reacted with acompound of the formula (B-112) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-113). A compound of the formula(B-113) is reacted with a compound of the formula (B-114), knowncompound or a compound prepared by known methods, in the presence of abase such as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, and the like, in the presence of a palladium catalystsuch as 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-115). A compound of the formula(B-115) is then reacted with an acid such as hydrochloric acid,hydrobromic acid, trifluoroacetic acid, acetic acid, formic acid, andthe like, optionally with heating, optionally with microwave irradiationto provide a compound of the formula (B-116). A compound of the formula(B-116) is reacted with an aldehyde in the presence of a reducing agentsuch as sodium triacetoxy borohydride, sodium borohydride, and the like,optionally in the presence of an acid such as acetic acid, formic acid,hydrochloric acid, and the like, in a solvent such as tetrahydrofuran,1,4-dioxane, methylene chloride, methanol, ethanol, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-117). Alternatively, a compound ofthe formula (B-116) is reacted with a ketone in the presence of areducing agent such as sodium triacetoxy borohydride, sodiumborohydride, and the like, optionally in the presence of an acid such asacetic acid, formic acid, hydrochloric acid, and the like, in a solventsuch as tetrahydrofuran, 1,4-dioxane, methylene chloride, methanol,ethanol, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (B-117).

A compound of the formula (B-118), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(B-119), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-120). A compound of the formula (B-120) is reacted with acompound of the formula (B-121) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-122). A compound of the formula(B-122) is reacted with a compound of the formula (B-123), knowncompound or a compound prepared by known methods, in the presence of abase such as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, and the like, in the presence of a palladium catalystsuch as 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-124).

A compound of the formula (B-125), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(B-126), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-127). A compound of the formula (B-127) is reacted with acompound of the formula (B-128) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-129). A compound of the formula(B-129) is reacted with a compound of the formula (B-130), knowncompound or a compound prepared by known methods, in the presence of abase such as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, and the like, in the presence of a palladium catalystsuch as 1,1′ (bisdiphenyl phosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-131).

A compound of the formula (B-132), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(B-133), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-134). A compound of the formula (B-134) is reacted with acompound of the formula (B-135) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-136). A compound of the formula(B-136) is reacted with a compound of the formula (B-137), knowncompound or a compound prepared by known methods, in the presence of abase such as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, and the like, in the presence of a palladium catalystsuch as 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-138).

A compound of the formula (B-139), a known compound or a compoundprepared by known methods, is reacted with a compound of the formula(B-140), a known compound or a compounds prepared by known methods, inthe presence of a base such as potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, and the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, N, N-dimethyl formamide, dimethylsulfoxide, methanol, ethanol, and the like, optionally with heating,optionally with microwave irradiation to provide a compound of theformula (B-141). A compound of the formula (B-141) is reacted with acompound of the formula (B-142) in the presence of a palladium catalystsuch as a 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone) dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof potassium acetate, in the presence of a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, N,N-dimethyl formamide, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-143). A compound of the formula(B-143) is reacted with a compound of the formula (B-144), knowncompound or a compound prepared by known methods, in the presence of abase such as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, and the like, in the presence of a palladium catalystsuch as 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II),tris(dibenzylideneacetone)dipalladium, palladiumtetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,acetonitrile, and the like, optionally in the presence of water,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-145).

A compound of the formula (B-146) is reacted with a compound of theformula (B-147), a known compound or a compounds prepared by knownmethods, in the presence of a base such as triethylamine,diisopropylethyl amine, pyridine, 2,6-lutidine, and the like, in thepresence of a solvent such as acetonitrile, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-148).

A compound of the formula (B-149) is reacted with hydrogen in thepresence of a palladium catalyst such as palladium on carbon,tris(dibenzylideneacetone)dipalladium, palladium,tetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methanol, ethanol,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (B-150).

A compound of the formula (B-151) is reacted with a compound of theformula (B-152), a known compound or a compounds prepared by knownmethods, in the presence of a base such as triethylamine,diisopropylethyl amine, pyridine, 2,6-lutidine, and the like, in thepresence of a solvent such as acetonitrile, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-153).

A compound of the formula (B-154) is reacted with hydrogen in thepresence of a palladium catalyst such as palladium on carbon,tris(dibenzylideneacetone)dipalladium, palladium,tetrakis(triphenylphosphine), palladium acetate, palladium chloride,(tridibenzylideneacetone) dipalladium(0), and the like, in the presenceof a solvent such as tetrahydrofuran, 1,4-dioxane, methanol, ethanol,and the like, optionally with heating, optionally with microwaveirradiation to provide a compound of the formula (B-155).

A compound of formula (B-156) is reacted with trimethylsilyldiazomethanein hexanes in the presence of a base such as lithium diisopropylamide,sodium diisopropylamide, potassium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and the like, in the presence of a solvent such as1,4-dioxane, tetrahydrofuran, methylene chloride, 1,2-dichloroethane,and the like, optionally with cooling to −78° C. to provide a compoundof formula (B-157). A compound of formula (B-157) is reacted with areducing hydride reagent such as sodium borohydride, lithiumborohydride, lithium aluminum hydide, and the like, in a solvent such asmethanol, ethanol, 1,4-dioxane, tetrahydrofuran, and the like,optionally with heating, optionally with microwave irradiation toprovide a compound of the formula (B-158). A compound of formula (B-158)is reacted with a compound of formula (B-159) a known compound orcompound prepared by known methods, in the presence of a phosphine suchas triphenylphosphine, tri(o-tolyl)phosphine,resin-boundtriphenylphosphine, and the like, in the presence of an azodicarboxylatesuch as diethyl azodicarboxylate, diisopropyl azodicarboxylate,di-t-butylazodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, and thelike, in the presence of a solvent such as tetrahydrofuran, diethylether, 1,4-dioxane, methylene chloride, and the like, optionally withheating, optionally with microwave irradiation to provide a compound ofthe formula (B-160).

A compound of the formula (B-161), a known compound or a compoundprepared by known methods, is reacted with borane dimethylsulfide in asolvent such as acetonitrile, N,N dimethylformamide, 1,4-dioxane,tetrahydrofuran, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (B-162).Alternatively, a compound of the formula (B-161), a known compound or acompound prepared by known methods, is reacted with methylene dibromidein a solvent such as acetonitrile, dimethylformamide, 1,4-dioxane,tetrahydrofuran, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (B-162).

A compound of the formula (B-163), a known compound or a compoundprepared by known methods, is reacted with borane dimethylsulfide in asolvent such as acetonitrile, N,N dimethylformamide, 1,4-dioxane,tetrahydrofuran, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (B-164).Alternatively, a compound of the formula (B-163), a known compound or acompound prepared by known methods, is reacted with methylene dibromidein a solvent such as acetonitrile, dimethylformamide, 1,4-dioxane,tetrahydrofuran, and the like, optionally with heating, optionally withmicrowave irradiation to provide a compound of the formula (B-164).

The compounds of formula (I) differ from the compounds made usingsynthetic schemes A-1 to A-31 (see above) and/or schemes B-1 to B-44(see above) in the substituents of the “head portion” that contains thebenzo[d][1,3]oxathiole, benzo[d][1,3]oxathiole 3-oxide orbenzo[d][1,3]oxathiole 3,3-dioxide (typically shown herein as theleftmost portion of the compound). Accordingly, synthesis of thecompounds of formula (I) involves many of the same synthetic steps asshown in schemes A-1 to A-31 and schemes B-1 to B-44, e.g. forsynthesizing the “tail portion” (typically shown herein as the rightmostportion of the compound) which does not include thebenzo[d][1,3]oxathiole, benzo[d][1,3]oxathiole 3-oxide orbenzo[d][1,3]oxathiole 3,3-dioxide. Exemplary synthetic schemes forproducing compounds of formula (I) are shown below.

In Schemes C-1a and C-1b above, with X⁶, X^(6′), X^(6″), X⁷ and X^(7′)as defined for the compounds of formula (I), compounds of formula (C-1a)or (C-1b) are commercially available or readily prepared by knownmethods. A compound of the formula (C-1a) or (C-1b) is reacted withtriflic anhydride in the presence of a base (such as, pyridine,2,6-lutidine, and the like) in a solvent (such as acetonitrile,tetrahydrofuran, 1,4-dioxane, methylene chloride, N,N-dimethylformamideand the like), optionally with heating, and optionally with microwaveirradiation, to provide a compound of the formula (C-2a) or (C-2b),respectively. A compound of formula (C-2a) or (C-2b) is reacted withbase (such as sodium hydroxide, potassium hydroxide, cesium hydroxidepotassium carbonate, cesium carbonate, and the like) in a solvent (suchas water, or a mixture of water with organic solvents, such as,tetrahydrofuran, 1,4-dioxane, and the like) with heating, optionallywith microwave irradiation, to provide a compound of the formula (C-3a)or (C-3b), respectively. A compound of formula (C-3a) or (C-3b) isreacted with a ketone (such as acetone, cyclobutanone, cyclopentatone,1,1,1,5,5,5-hexafluoropentan-3-one, and the like) in the presence of anacid (such as p-toluenesulfonic acid and the like) or alternatively, inthe presence of a base (such as sodium hydroxide, potassium hydroxide,and the like), and in the presence of a solvent (such as benzene,toluene and the like) with heating, optionally with microwave, andoptionally with Dean-Stark attachment to produce a compound of formula(C-4a) or (C-4b), respectively. Alternatively, for certain compounds offormula (I), a compound of formula (C-3a) or (C-3b) is reacted withmono- or difluorinated dihalogenomethane (e.g. difluorodibromomethane,dibromofluoromethane, and the like) in the presence of a base (such aspotassium carbonate, cesium carbonate, trimethylamine, pyridine, and thelike), in a solvent (such as acetonitrile, methylene chloride,N,N-dimethylformamide, and the like), optionally in the presence of aphase transfer catalyst (e.g. crown ether such as 18-crown-6,12-crown-4, and the like), optionally with heating, and optionally withmicrowave irradiation to provide a compound of the formula (C-4a) or(C-4b), respectively. The resulting compound of formula (C-4a) or (C-4b)may be used in Scheme C-2 below or may be further reacted with hydrogenperoxide or meta-chloroperbenzoic acid, or the like, in a solvent (suchas acetic acid, chloroform, dichloromethane, and the like), optionallywith heating, and optionally with microwave irradiation, to provide acompound of formula (C-5a) or (C-5b), respectively.

Synthesizing the tail portion can proceed as has already been describedin schemes A-1 to A-31 (see above) and schemes B-1 to B-44 (see above).For example, with reference to Scheme C-2 above, a compound of theformula (C-6) in which X¹, X², X⁶, X^(6′), X^(6″), X⁷ and X^(7′) are asdefined for the compounds of formula (I) (e.g. a compound of formula,C-4a, C-4b, C-5a or C-5b) is reacted with a boronic acid/ester offormula (C-7), in which X³, X⁴ and A are as defined for the compounds offormula (I), in the presence of a base (such as potassium acetate,sodium carbonate, cesium carbonate, lithium carbonate, potassiumcarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, andthe like) in the presence of a palladium catalyst (such as palladiumacetate, tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and thelike) in the presence of a solvent (such as acetonitrile, acetone,tetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane,and the like), optionally with heating, and optionally with microwaveirradiation, to provide a compound of formula (C-8). Exemplary compoundsof formula (C-7) include, without limitation, a boronic acid/ester asalready described above, e.g. compound A-10 (see schemes A-3 to A-13,A-16 and A-17), compound A-35 (see scheme A-14), compound A-45 (seescheme A-15), compound A-60 (see scheme A-19), compound A-68 (see schemeA-20), compound A-70 (see scheme A-21), compound A-76 (see scheme A-22),compound A-84 (see scheme A-23), compound A-91 (see scheme A-24),compound A-98 (see scheme A-25), compound A-105 (see scheme A-26),compound B-17 (see schemes B-6 to B-8), compound B-29 (see scheme B-9),compound B-29a (see scheme B-10), compound B-30 (see scheme B-11),compound B-30a (see scheme B-12), compound B-41 (see schemes B-15 toB-22, B-24 and B-28), compound B-66 (see scheme B-25), compound B-77(see scheme B-26), compound B-95 (see scheme B-30), compound B-104 (seescheme B-31), compound B-107 (see scheme B-32), compound B-113 (seescheme B-33), compound B-122 (see scheme B-34), compound B-129 (seescheme B-35), compound B-136 (see scheme B-36) and compound B-143 (seescheme B-37), and the boronic acids/esters described in Examples A-7,A-26, A-39, A-45, A-60, A-70, A-73, A-79, A-85, A-88, A-91, B-8, B-11,B-49, B-55, B-74, B-80, B-83 and B-90 (shown below). In each case, the Agroup for the compounds of formula (C-8) would be identical to thoseindicated in the products shown for schemes A-1 to A-31 and schemes B-1to B-44.

Alternatively, referring now to Scheme C-3, a compound of formula (C-6)(defined above) can be reacted with a compound of formula (C-9) underthe same conditions described for Scheme C-2 to produce a compound offormula (C-10). The compound of formula (C-10) can be substituted forcompound A-55 in scheme A-18 to produce further substituted derivativesof the products shown therein (e.g. derivatives of A-57 and A-59).

Referring now to Scheme C-4 above, a compound of formula (C-11) (e.g.see synthesis of A-120 in scheme A-31 above) is reacted with a compoundof formula (C-10) (defined above) in the presence of a phosphine (suchas triphenylphosphine, tri(o-tolyl)phosphine,resin-boundtriphenylphosphine, and the like), in the presence of anazodicarboxylate (such as diethyl azodicarboxylate, diisopropylazodicarboxylate, di-t-butylazodicarboxylate,di-(4-chlorobenzyl)azodicarboxylate, and the like), in the presence of asolvent (such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methylenechloride, and the like), optionally with heating, and optionally withmicrowave irradiation, to provide a compound of formula (C-12).

Referring now to Scheme C-5 above, a compound of formula (C-15), a knowncompound or a compounds prepared by known methods, is reacted with acompound of formula (C-10) (defined above) in the presence of aphosphine (such as triphenylphosphine, tri(o-tolyl)phosphine,resin-boundtriphenylphosphine, and the like), in the presence of anazodicarboxylate (such as diethyl azodicarboxylate, diisopropylazodicarboxylate, di-t-butylazodicarboxylate,di-(4-chlorobenzyl)azodicarboxylate, and the like), in the presence of asolvent (such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methylenechloride, and the like), optionally with heating, and optionally withmicrowave irradiation, to provide a compound of formula (C-16).

Referring now to Scheme C-6 above, a compound of the formula (C-16)(defined above) is reacted with a compound of the formula (C-17), aknown compound or a compounds prepared by known methods, in the presenceof a base (such as triethylamine, diisopropylethyl amine, pyridine,2,6-lutidine, and the like), in the presence of a solvent (such asacetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, andthe like), optionally with heating, and optionally with microwaveirradiation, to provide a compound of the formula (C-18).

Referring now to Scheme C-7 above, a compound of formula (C-18) (definedabove) is reacted with hydrogen in the presence of a palladium catalyst(such as palladium on carbon, tris(dibenzylideneacetone)dipalladium,palladium, tetrakis(triphenylphosphine), palladium acetate, palladiumchloride, (tridibenzylideneacetone) dipalladium(0), and the like), inthe presence of a solvent (such as tetrahydrofuran, 1,4-dioxane,methanol, ethanol, and the like,) optionally with heating, andoptionally with microwave irradiation, to provide a compound of formula(C-19).

Referring now to Scheme C-8, a compound of formula (C-20) is reactedwith trimethylsilyldiazomethane in hexanes in the presence of a base(such as lithium diisopropylamide, sodium diisopropylamide, potassiumdiisopropylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide, and the like), inthe presence of a solvent (such as 1,4-dioxane, tetrahydrofuran,methylene chloride, 1,2-dichloroethane, and the like), optionally withcooling to −78° C., to provide a compound of formula (C-21). A compoundof formula (C-21) is reacted with a reducing hydride reagent (such assodium borohydride, lithium borohydride, lithium aluminum hydide, andthe like), in a solvent (such as methanol, ethanol, 1,4-dioxane,tetrahydrofuran, and the like), optionally with heating, and optionallywith microwave irradiation, to provide a compound of formula (C-22). Acompound of formula (C-22) is reacted with a compound of formula (C-23),a known compound or compound prepared by known methods in which X³, X⁴,X⁶, X^(6′), X^(6″), X⁷ and X^(7′) are as defined for compounds offormula (I), in the presence of a phosphine (such as triphenylphosphine,tri(o-tolyl)phosphine,resin-bound triphenylphosphine, and the like), inthe presence of an azodicarboxylate (such as diethyl azodicarboxylate,diisopropyl azodicarboxylate, di-t-butylazodicarboxylate,di-(4-chlorobenzyl)azodicarboxylate, and the like), in the presence of asolvent (such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methylenechloride, and the like), optionally with heating, and optionally withmicrowave irradiation, to provide a compound of the formula (C-24).

VI. Exemplary Compounds Example A-1:6-(Benzyloxy)benzo[d][1,3]oxathiole-2-one

6-(Hydroxy)benzo[d][1,3]oxathiole-2-one (100 g, 0.6 mol) was dissolvedin acetonitrile (1000 mL) and treated with potassium carbonate (165 g,1.2 mol) and benzyl bromide (77.8 mL, 0.66 mol). The reaction mixturewas stirred overnight at 70° C. Upon cooling to ambient temperature theinorganic precipitate was filtered off and the filtrate was concentratedunder reduced pressure to a volume of 150 mL. Upon cooling, aprecipitate was formed, filtered off and washed with diethyl ether toafford (123.3 g, 80%) of the title compound which was used in the nextstep without further purification.

Example A-2: 6-((Benzyloxy)benzo[d][1,3]oxathiole

To a solution of 6-(benzyloxy)benzo[d][1,3]oxathiole-2-one (78.2 g, 0.3mol) in dibromomethane (235 mL) and water (16 mL) was added potassiumcarbonate (125.5 g, 0.9 mol) 18-crown-6 (2.0 g, 7.5 mmol). The reactionmixture was heated to reflux under argon for 48 hours. Upon cooling toambient temperature, an inorganic precipitate was formed and filteredoff and the filtrate was concentrated under reduced pressure. Theresidual oil was treated with dichloromethane (400 mL) and the organiclayer was separated, washed with brine (2×100 mL) and dried overmagnesium sulfate and filtered. The filtrate was evaporated underreduced pressure and the residual oil was treated with dry diethyl ether(200 mL) with cooling in dry ice-acetone bath and starred for 30minutes. The formed precipitate was filtered off and washed with colddiethyl ether (100 mL) to afford upon drying the title compound (62.5 g,85%) which was used in the next step without further purification.

Example A-3: 6-(Benzyloxy)-2H-benzo[d][1,3]oxathiole 3,3-dioxide

A solution of hydrogen peroxide (125 mL, 30% water) was added to asolution of 6-((benzyloxy)benzo[d][1,3]oxathiole (62.5 g, 0.26 mol) inacetic acid (625 mL) and the reaction mixture was stirred overnight at70° C. Upon cooling to ambient temperature, the reaction mixture wasquenched with water (625 mL) to form a precipitate which was filteredoff and washed with water (2×100 mL) to afford upon drying6-(benzyloxy)-2H-benzo[d][1,3]oxathiole 3,3-dioxide (61.7 g, 87%) whichwas used in the next step without further purification.

Example A-4: 6-Hydroxy-2H-benzo[d][1,3]oxathiole 3,3-dioxide

To a solution of 68 g (0.25 mol) of6-(benzyloxy)-2H-benzo[d][1,3]oxathiole 3,3-dioxide (68 g, 0.25 mol) intetrahydrofuran (816 mL) was added 10% Pd/C (6.8 g). The reactionmixture was stirred under hydrogen at ambient pressure and temperatureovernight and then filtered through a pad of celite. The filtrate wasevaporated under reduced pressure and the residual oil was trituratedwith diethyl ether (100 mL) and dried to afford6-hydroxy-2H-benzo[d][1,3]oxathiole 3,3-dioxide (39.3 g, 86%) which wasused in the next step without further purification.

Example A-5: 3,3-Dioxido-2H-benzo[d][1,3]oxathiol-6-ylTrifluoromethanesulfonate

To a solution of 6-hydroxy-2H-benzo[d][1,3]oxathiole 3,3-dioxide (39.2g, 0.21 mol) in pyridine (392 mL) was slowly added at 0° C. triflicanhydride (39 mL, 0.23 mol). The reaction mixture was then stirred for40 minutes at 0° C. and overnight at ambient temperature. The solventswere evaporated under reduced pressure and the residual oil was stirredin ethyl acetate (400 mL) to form a suspension which was washed with anaqueous solution citric acid (100 mL, 10%) followed by brine (100 mL)and water (100 mL). The organic layer was separated, dried overmagnesium sulfate and filtered. The filtrate was evaporated underreduced pressure to give an oil which was washed with diethyl ether (100mL) and the solution was reduced in vacuo to give an oil which waspurified by column chromatography eluting with dichloromethane to affordthe title compound (6.8 g, 85%) as a white powder: ¹H NMR (400 MHz,DMSO-d₆) δ 8.13 (d, J=8.7 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.43 (dd,J=8.6, 2.08 Hz, 1H), 5.54 (s, 2H).

Example A-6:tert-Butyl-4-((4-bromo-2-fluorophenoxy)methyl)piperidine-1-carboxylate

A suspension containingtert-butyl-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (80.0g, 0.27 mol), 4-bromo-2-fluorophenol (62.5 g, 0.33 mol) and potassiumcarbonate (75.4 g, 0.55 mol) in dimethylsulfoxide (800 mL) was stirredat 110° C. for 16 hours. Upon completion of reaction as evidenced bythin layer chromatography, dimethylsulfoxide was distilled off underreduced pressure. The residual oil was quenched with water (800 mL) andthe resultant precipitate was filtered off and re-crystallized fromiso-propanol to affordtert-butyl-4-((4-bromo-2-fluorophenoxy)methyl)pyperidine-1-carboxylate(88.0 g, 83.1%) as a white crystalline powder: ¹H NMR (400 MHz, DMSO-d₆)δ 7.50 (dd, J=10.85, 2.3 Hz, 1H), 7.30 (m, 1H), 7.15 (m, 1H), 3.96 (d,J=10.7 Hz, 2H), 3.90 (d, J=6.4 Hz, 2H), 2.66-2.79 (m, 2H), 1.89-1.98 (m,1H), 1.72 (d, J=10.9 Hz, 2H), 1.39 (s, 9H), 1.09-1.23 (m, 2H).

Example A-7:tert-Butyl-4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy)methyl)piperidine-1-carboxylate

To a mixture oftert-butyl-4-((4-bromo-2-fluorophenoxy)methyl)piperidine-1-carboxylate(60.0 g, 0.15 mol) and4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane (51.0 g, 0.2mol) in acetonitrile (1000 mL) was added of 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) (Pd(dppf)Cl₂(5.63 g, 8 mmol) and potassium acetate (45.5 g, 0.46 mol) and thesolution was stirred under argon at 70° C. for 16 hours. Uponcompletion, the reaction mixture was diluted with ethyl acetate (1000mL) and washed with brine (1000 mL). The organic layers were combined,dried over magnesium sulfate, filtered and the filtrate was evaporatedunder reduced pressure. The residue after evaporation was purified bycolumn chromatography eluting with hexanes-ethyl acetate mixture (10: 1)to afford the title compound (50.0 g, 74.3%) as a white powder. ¹H NMR(400 MHz, DMSO-d₆) δ 7.42 (d, J=8.1 Hz, 1H), 7.31 (m, 1H), 7.15 (m, 1H),3.91-4.02 (m, 4H), 2.66-2.80 (m, 2H), 1.89-2.02 (m, 1H), 1.73 (d, J=11.2Hz, 2H), 1.39 (s, 9H), 1.27 (s, 12H), 1.07-1.22 (m, 2H).

Example A-8:Tert-Butyl-4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate

A mixture oftert-butyl-4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy]methyl)piperidine-1-carboxylate(36.1 g, 83 mmol), 3,3-dioxido-1,3-benzoxythiol-6-yl trifluoromethanesulfonate (26.5 g, 83 mmol), potassium carbonate (69.0 g, 0.5 mmol) andof 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (3.1 g, 4 mmol) in water-dioxane mixture (1000 mL, 1:1) wasstirred under argon at ambient temperature for 1 hour. A precipitate wasformed, filtered off and was subjected to purification by columnchromatography on silica gel eluting with dichloromethane to affordcrude product which was dissolved in dioxane (200 mL) and stirred withthe Lewatit® MonoPlus SP 112 acidic resin (5.0 g) at ambient temperaturefor 2 hours. The solution was filtered and the filtrate was evaporatedto afford the title compound (28.4 g, 71.5%). as a white powder. ¹H NMR(400 MHz, DMSO-d₆) δ 7.89 (d, J=8.1 Hz, 1H), 7.71 (dd, J=12.9, 1.9 Hz,1H), 7.62 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.28 (t, J=8.7 Hz, 1H), 5.43(s, 2H), 3.94-4.02 (m, 4H), 2.67-2.85 (m, 2H), 1.93 (m, 1H), 1.74 (d,J=11.6 Hz, 2H), 1.40 (s, 9H), 1.11-1.24 (m, 2H).

Example A-9:6-((3-Fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide Hydrochloride

To a solution oftert-butyl-4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine-1-carboxylate(24.0 g, 50 mmol) in dioxane (350 mL) was added 50 mL of hydrochlorideacid solution (4M) in dioxane and the resulting mixture was stirred at70° C. for 24 hours. Upon cooling to ambient temperature a precipitatewas formed which was filtered off to afford upon drying the titlecompound (19.5 g, 93.7%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ9.01 (br s, 1H), 8.69 (br s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.73 (dd,J=12.8, 2.3 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.31 (t,J=8.8 Hz, 1H), 5.44 (s, 2H), 4.02 (d, J=6.3 Hz, 2H), 3.29 (d, J=12.5 Hz,2H), 2.90 (m, 2H), 2.11 (br. s, 1H), 1.92 (d, J=12.7 Hz, 2H), 1.57 (m,2H).

Example A-10:6-((3-Fluoro-4-((1-isopropylpiperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (200 mg, 0.48 mmol) in acetone (20 mL) wasadded sodium triacetoxyborohydride (307 mg, 1.44 mmol) and the mixturewas stirred at ambient temperature for 16 hours. Upon completion, thereaction mixture was evaporated under reduced pressure and the residualoil was treated with 10% aqueous solution of K₂CO₃ (30 mL) and stirredat ambient temperature for 30 minutes. A formed precipitate wasfiltered, dried and purified by column chromatography, eluting with agradient CH₂Cl₂:MeOH:25% aq.NH₄OH mixture(600:10:1-400:10:1-30:10:1-200:10:1) to afford the title compound as awhite powder. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=8.0 Hz, 1H),7.67-7.74 (m, 1H), 7.53-7.65 (m, 3H), 7.27 (t, J=8.8 Hz, 1H), 5.43 (s,2H), 3.96 (d, J=5.6 Hz, 2H), 3.96 (d, J=5.6 Hz, 2H), 2.6-2.87 (m, 3H),2.03-2.18 (m, 2H), 1.67-1.81 (m, 3H), 1.2-1.36 (m, 2H), 0.96 (d, J=6.4Hz, 6H).

Example A-11: 1-tert-Butylpiperidine-4-carbaldehyde

To a solution of diisopropylamine (19.65 g, 194.2 mmol) intetrahydrofuran (72 mL) at −15° C. was added n-butyllithium (2.5M inhexanes, 9.36 mL, 23.4 mmol) and the mixture was cooled to −78° C. Tothe reaction mixture was added to trimethylsilyldiazomethane (2M inhexanes, 11.7 mL, 23.4 mmol) at −75° C., and the resulting mixture wasstirred at −78° C. for 1 hour. To the reaction mixture was added asolution of 1-tert-butylpiperidine-4-one (3.0 g, 19.3 mmol) intetrahydrofuran (10 mL) at −75° C., and the resulting mixture wasstirred at −78° C. for 1.5 hours then allowed to warm up to ambienttemperature and then stirred overnight under reflux. To the reactionmixture was added water (50 mL) and the volatiles were evaporated underreduced pressure and water (100 mL) was added and the resulting mixturewas extracted with EtOAc (3×50 mL). The organic layer was separated,washed with brine (100 mL), dried over Na₂SO₄ and filtered. The filtratewas evaporated under reduced pressure and the residual oil was dissolvedin EtOAc (120 mL) and silica gel (24 g) was added at room temperature.The mixture was stirred at ambient temperature for 1.5 h, filtered andthe filtrate was evaporated under reduced pressure to afford the titlecompound. ¹H-NMR (400 MHz, CDCl₃) δ 9.64 (s, 1H), 2.92-3.02 (m, 2H),2.16-2.27 (m, 2H), 1.87-1.96 (m, 2H), 1.61-1.82 (m, 3H), 1.07 (s, 9H).

Example A-12: (1-tert-Butylpiperidin-4-yl)methanol

To a solution of 1-tert-butylpiperidine-4-carbaldehyde (2.1 g, 12.4mmol) in methanol (50 mL) was added sodium borohydride (0.5 g, 12.4mmol) and the mixture was stirred at ambient temperature for 30 minutes.Upon completion the reaction mixture was evaporated under reducedpressure and the residue was treated with 10% aq. solution of potassiumcarbonate (50 mL) and the resulting suspension was extracted withdichloromethane (3×30 mL). The combined extracts were washed with brine(50 mL), dried over sodium sulfate, filtered, and the filtrate wasevaporated to afford the title compound. ¹H-NMR (400 MHz, CDCl₃) δ3.03-3.12 (m, 2H), 2.02-2.15 (m, 2H), 1.57-1.83 (m, 3H), 1.41-1.56 (m,1H), 1.21-1.35 (m, 2H), 1.03-1.18 (m, 11H).

Example A-13:6-((3-Fluoro-4-((1-tert-butylpiperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a solution of (1-tert-butylpiperidin-4-yl)methanol (150 mg, 0.88mmol), 4-(3,3-dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenol (171 mg,0.613 mmol) and triphenylphosphine (459 mg, 1.75 mmol) intetrahydrofuran (9 mL) was added dropwise diisopropyl azodicarboxylate(354 mg, 1.75 mmol) at 0° C., and the resulting mixture was stirred atambient temperature for 24 hours. Upon completion, water (40 mL) wasadded and the reaction mixture was extracted with ethyl acetate (2×50mL). The organic layer was separated and washed with 1M aq. Solution ofpotassium hydroxide (30 mL), brine (50 mL) and dried over sodiumsulfate. The reaction mixture was filtered and the filtrate wasevaporated to give an oil which was purified by column chromatography onsilica gel eluting with CH₂Cl₂:MeOH:25% NH₄OH mixture (20:1:0.1) toobtain a white solid which was purified further by preparative HPLC toafford the title compound (34.4 mg, 9%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 7.89 (d, J=8.0 Hz, 1H), 7.66-7.74 (m, 1H), 7.52-7.64 (m,3H), 7.19-7.32 (m, 1H), 5.43 (s, 2H), 3.92-4.19 (m, 1H), 2.92-3.12 (m,1H), 2.57-2.8 (m, 2H), 1.44-2.16 (m, 6H), 0.91-1.33 (m, 10H) LCMSretention time 5.3 minutes, [M+1]⁺ 434

Example A-14:4-((4-3,3-Dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyoxy)methyl)-N,N-dimethylpiperidine-1-carboxamide

To a solution of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (0.25 g, 0.6 mmol) and triethylamine (0.15 g,1.5 mmol) in acetonitrile (50.0 mL) at 0° C. was added dropwisedimethylcarbamic chloride (750 mg, 7.0 mmol). The reaction mixture wasstirred at 70° C. for 24 hours. Upon completion, the reaction mixturewas diluted with ethyl acetate (50 mL) and washed with 0.1N aq solutionof hydrochloric acid (20 mL) and brine (20 mL). The organic layer wasdried over sodium sulfate and concentrated in vacuo to afford the titlecompound (0.23 g, 85.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.89 (d, J=8.2 Hz, 2H), 7.72 (dd, J=12.9, 1.84 Hz, 1H), 7.62 (s, 1H),7.58 (dd, J=8.1, 1.59 Hz, 2H), 7.29 (t, J=8.8 Hz, 1H), 5.43 (s, 2H),3.99 (d, J=6.4 Hz, 3H), 3.56 (d, J=12.1 Hz, 2H), 2.72 (m, 8H), 1.96 (s,1H), 1.75 (d, J=11.3, 2H), 1.27 (m, 2H).

Example A-15:1-4-((4-3,3-Dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyoxy)Methyl)-piperidin-1-yl)-2,2-dimethylpropan-1-one

To a suspension of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (0.25 g, 0.6 mmol) and pivalic acid (72 mg,0.7 mmol) in acetonitrile (10 mL) was added triethylamine (0.18 mg, 1.8mmol) followed byN-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminiumhexafluoro-phosphate (HBTU, 265 mg, 0.7 mmol). The resulting mixture wasstirred at 40° C. for 24 hours. Upon cooling a precipitate was filteredoff and dried to afford the title compound (156 mg, 56%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=8.19 Hz, 1H), 7.74 (dd,J=12.84 Hz, J=2.1 Hz 1H), 7.62 (s, 1H), 7.58 (m, 2H), 7.29 (t, J=8.7 Hz,1H), 5.44 (s, 2H), 4.30 (d, J=13.8 Hz, 2H), 4.00 (d, J=6.4 Hz, 2H), 2.82(d, J=12.1 Hz, 2H), 2.08 (s, 1H), 1.80 (d, J=12.8 Hz, 2H), 1.2 (m, 12H).

Example A-16: Tert-Butyl(2-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-2-oxoethyl)carbamate

To a suspension of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (0.25 g, 0.6 mmol) andN-(tert-butoxycarbonyl)glycine (0.12 g, 0.7 mmol) in acetonitrile (10mL) was added triethylamine (0.182 g, 1.8 mmol), followed byN-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminiumhexafluorophosphate (HBTU, 0.3 g, 0.8 mmol). The resulting mixture wasstirred at 40° C. for 24 hours. Upon completion acetonitrile was removedunder reduced pressure and the residue was treated with water (20 mL). Asolid precipitate was filtered off and dried to afford the titlecompound (0.3 g, 93.5%) as a white solid. The product was used in thenext step without further purification.

Example A-17:(2-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)Methyl)piperidin-1-yl)ethan-1-one

A solution of tert-butyl(2-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-2-oxoethyl)carbamate(1.2 g, 2.3 mmol) of in dioxane (15 mL) was treated with 4M hydrochloricacid in dioxane (3 mL) and stirred at 70° C. for 24 hours. Upon coolingto ambient temperature a precipitate was formed which was filtered andsuspended in 30 mL of 1 M solution of potassium carbonate in water. Aprecipitate was filtered to afford upon drying the title compound (0.17g, 65%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=8.2 Hz,2H), 7.71 (dd, J=12.8, 2.0 Hz, 2H), 7.61 (s, 1H), 7.61 (s, 1H), 7.58(dd, J=8.25, 7.28 (t, J=8.80 Hz, 2H), 5.43 (s, 2H), 1.14 (m, 2H), 4.40(d, J=12.35 Hz, 1H), 3.99 (d, J=6.5 Hz, 3H), 3.76 (d, J=14.3 Hz, 2H),3.32 (m, 3H), 2.97 (t, J=12.2 Hz, 1H), 2.62 (t, J=12.2 Hz, 1H), 2.06 (s,1H), 1.78 (d, J=12.1 Hz 2H), 1.56 (s, 2H), 1.28 Hz, 2H).

Example A-18: tert-Butyl(S)-(1-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

A mixture of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[1,3]oxathiole3,3-dioxide hydrochloride (0.23 g, 0.57 mmol),N-(tert-butoxycarbonyl)-L-valine (0.12 g, 0.57 mmol),diisopropylethylamine (0.147 g, 1.14 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl, 1.11 g, 0.57 mmol)was stirred at ambient temperature for 12 hours. The solvent was thenevaporated in vacuo and water (50 mL) was added. The product wasextracted with dichloromethane (3×20 mL). The combined extracts wereevaporated to give an oil which was subjected to column chromatographyon silica gel eluting with dichloromethane to afford the title product(0.2 g, 61%) as a white solid. The material was used in the next stepwithout further purification.

Example A-19:((S)-2-Amino-1-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-)-3-methylbutan-1-one

A solution of tert-butyl(S)-(1-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate(0.2 g, 0.35 mmol) in methylene chloride (20 mL) was treated with 4Msolution of HCl in dioxane (4 mL, 1.0 mmol) and the resulting mixturewas stirred at ambient temperature for 3 hours. A precipitate wasformed, filtered and washed with ether to afford upon drying the titlecompound (0.15 g, 84%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.10 (bs, 3H), 7.89 (d, J=8.2 Hz, 1H), 7.72 (d, J=12.7 Hz, 1H),7.64-7.55 (m, 3H), 7.33-7.26 (m, 1H), 5.43 (s, 2H), 4.46 (t, J=14.3 Hz,1H), 4.34-4.21 (m, 1H), 4.05-3.97 (m, 3H), 3.12 (t, J=12.4 Hz, 1H), 2.73(t, J=12.3 Hz, 1H), 2.19-2.00 (m, 2H), 1.94-1.80 (m, 2H), 1.40-1.14 (m,2H), 1.00 (m, 3H), 0.91 (m, 3H).

Example A-20:4-((4-3,3,-Dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyoxy)methyl)-piperidine-1-carboxamide

To a solution of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (0.25 g, 0.6 mmol) and triethylamine (0.15 g,1.5 mmol) in acetonitrile (50.0 mL) at 0° C. was added dropwiseisocyanato(trimethyl)silane (0.08 g, 7.0 mmol). The reaction mixture wasstirred at 70° C. for 24 hours and then washed sequentially with 0.1 Naqueous hydrochloric acid (20 mL) and brine (40 mL). The organic layerwas separated, dried over sodium sulfate, filtered and the filtrate wasconcentrated in vacuo to afford the title compound (0.18 g, 71%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=8.1 Hz, 1H), 7.73(s, 1H), 7.62 (m, 1H), 7.28 (t, J=8.7 Hz, 1H), 5.88 (s, 2H), 5.43 (s,2H), 3.99 (d, J=6.0 Hz, 2H), 3.95 (s, 2H), 2.68 (t, J=12.2 Hz, 2H), 1.96(m, 1H), 1.70 (d, J=12.2 Hz, 2H), 1.18 (m, 2H).

Example A-21:1-4-((4-3,3,-Dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyoxy)Methyl)-piperidin-1-yl)-2-methylpropan-1-one

To a suspension of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (0.25 g, 0.6 mmol) and 2-methylpropanoic acid(0.062 g, 0.7 mmol) in acetonitrile (10 mL) was added triethylamine(0.182 g, 1.8 mmol). To a resulting solution was addedN-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminiumhexafluoro phosphate (HBTU, 300 mg, 0.8 mmol). The resulting mixture wasstirred at 40° C. for 24 hours. Upon cooling a formed precipitate wasfiltered off to afford upon drying the title compound (0.108 g, 40%) asan off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=8.1 Hz, 1H),7.69 (dd, J=12.9, J=2.0 Hz, 1H), 7.59 (m, 3H), 4.42 (d, J=13.2, 1H),4.00 (m, 3H), 3.05 (t, J=11.9, 1H), 2.88 (q, J=6.9 Hz, 1H), 2.5 (m, 1H),2.07 (m, 1H), 1.82 (m, 2H), 7.30 (t, J=8.7, 1H), 1.20 (m, 2H), 0.98 (d,J=5.9 Hz, 6H).

Example A-22:Ethyl-2-(4-((-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluoropheny-oxy)methyl)-piperidin-1-yl)acetate

To a solution of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (1000 mg, 2.4 mmol) and ethyl oxoacetate (271mg, 2.6 mmol) and triethylamine (269 mg, 2.6 mmol) in dichloromethane(30 mL) at ambient temperature was added sodium triacetoxyborohydride(768 mg, 3.6 mmol) in small portions. The reaction mixture was stirredat room temperature for 15 hours and upon completion was washed withwater (3×10 mL). The organic phase was separated and the volatiles wereremoved under reduced pressure. The oily residue after evaporation wastriturated with acetonitrile (5 mL) to afford the title compound (716mg, 65%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d,J=8.9 Hz, 1H), 7.71 (d, J=12.8 Hz, 1H, 5.43 (s, 2H), 1.19 (t, J=7.1 Hz,3H), 7.54-7.63 (m, 3H), 7.27 (t, J=8.9 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H),3.98 (d, J=5.9 Hz, 2H), 3.19 (s, 2H), 1.27-1.41 (m, 2H), 2.86 (d, J=10.5Hz, 2H), 2.18 (t, J=10.5 Hz, 2H), 1.67-1.83 (m, 3H).

Example A-23:2-(4-((4-(3,3-Dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyoxy)Methyl)-piperidin-1-yl)acetic Acid

To a suspension ofethyl-2-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyoxy)methyl)-piperidin-1-yl)acetate(0.5 g, 1.1 mmol) in ethanol (2 mL) was added a solution of potassiumhydroxide (73 mg, 1.3 mmol) in water (0.5 mL) and the reaction mixturewas stirred at ambient temperature for 16 hours. Upon completion, thereaction mixture was acidified with 1N hydrochloric acid solution to pH5. The solution was then filtered to remove a precipitate, washed withwater (10 mL) and dried to afford the title compound (440 mg, 93%) as awhite powder ¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=8.9 Hz, 1H), 7.72(d, J=12.8 Hz, 1H), 7.55-7.63 (m, 3H), 7.29 (t, J=8.9 Hz, 1H), 5.43 (s,2H), 4.00 (d, J=5.9 Hz, 2H), 3.21 (s, 2H), 1.43-1.58 (m, 2H), 3.19 (d,J=10.5 Hz, 2H), 2.57 (t, J=10.5 Hz, 2H), 1.76-1.98 (m, 3H).

Example A-24:6-(4-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

A solution of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (0.23 g, 0.57 mmol),2-chloro-5-ethylpyrimidine (0.086 g, 0.6 mmol) and triethylamine (0.23g, 2.3 mmol) in acetonitrile (50 mL) was stirred at reflux for 6 hours.Upon completion the reaction mixture was allowed to reach roomtemperature and filtered to remove a precipitate. The filtrate waswashed consequently with water and hexanes and then purified by columnchromatography eluting with dichloromethane to provide the title product(0.2 g, 74%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 2H), 7.89 (d, J=7.8Hz, 1H), 7.71 (d, J=12.5 Hz, 1H), 7.64-7.55 (m, 3H), 7.29 (t, J=8.2 Hz,1H), 5.44 (s, 2H), 4.67 (d, J=12.1 Hz, 2H), 4.01 (d, J=5.6 Hz, 2H), 2.89(t, J=12.1 Hz, 2H), 2.46-2.39 (m, 2H), 2.10 (bs, 1H), 1.84 (d, J=11.7Hz, 2H), 1.30-1.19 (m, 2H), 1.13 (t, J=7.3 Hz, 3H).

Example A-25: tert-Butyl4-(((5-bromopyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate

To a mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(18.37 g, 0.085 mol) and 5-bromo-2-chloropyrimidine (15.0 g, 0.077 mol)in tetrahydrofuran (200 mL) was added a suspension (60%) of sodiumhydride (3.07 g, 0.128 mol) in mineral oil and the resulting mixture wasstirred under argon at 70° C. for 16 hours. Upon completion ethanol (15mL) was slowly added to the reaction mixture and the reaction mixturewas diluted with ethyl acetate (200 mL) and washed with brine (100 mL).The organic phase was separated, dried over magnesium sulfate, filteredand the filtrate was evaporated under reduced pressure. The residueafter evaporation was subjected to column chromatography eluting withhexanes-ethyl acetate mixture 5:1 by volume to afford 15.13 g (52.4%) oftert-butyl 4-(((5-bromo-pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate as a white powder. The product wasused in the next step without further purification.

Example A-26: Tert-Butyl4-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(((5-bromopyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate (11.0 g,0.03 mol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane(7.5 g. 0.03 mol) and 1,1′ (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (1.0 g, 1.3 mmol) and potassiumacetate (8.7 g, 0.09 mol) in acetonitrile (300 mL) was stirred underargon at 70° C. for 16 hours. Upon completion, the reaction mixture wasdiluted with ethyl acetate (200 mL) and washed with brine (100 mL). Theorganic phase was separated, dried over magnesium sulfate, filtered andthe filtrate was evaporated under reduced pressure. The residue afterevaporation was subjected to column chromatography eluting withhexanes-ethyl acetate mixture 8:1 by volume to afford the title compound(4.5 g, 36.4%) as a white powder. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (s,2H), 1.27 (m, 2H), 4.26 (s, J=6.7 Hz, 2H), 4.14 (m, 2H), 2.74 (t, J=12.9Hz, 2H), 2.02 (m, 1H), 1.84 (d, J=13.2 Hz, 2H), 1.46 (s, 9H), 1.35 (s,12H).

Example A-27: Tert-Butyl4-(((5-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy}methyl)piperidine-1-carboxylate(2.77 g, 6.7 mmol), 3,3-dioxido-1,3-benzoxythiol-6-yl trifluoromethanesulfonate (1.57 g, 4.9 mmol), potassium carbonate (4.0 g, 29.4 mmol) and1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂(0.36 g, 0.5 mmol) in water-dioxane mixture 1:1 by volume (50 mL) wasstirred under argon at ambient temperature for 1 hour and then filtered.The solid was purified by column chromatography on silica gel elutingwith dichloromethane to afford the crude product. This material wasdissolved in dioxane (30 mL) and stirred with the Lewatit® MonoPlusSP-112 resin (0.5 g) for 2 hours and then filtered. The solvent wasdistilled off to afford the title compound (1.66 g, 73.4%) as a whitepowder. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 2H), 7.97 (d, J=8.1 Hz,1H), 7.74 (s, 1H), 7.66 (d, J=8.16 Hz, 1H), 5.45 (s, 2H), 4.24 (d, J=6.5Hz, 2H), 3.97 (d, J=11.8, Hz, 2H), 2.74 (m, 2H), 1.98 (m, 1H), 1.98 (m,1H), 1.72 (m, J=12.4 Hz, 2H), 1.17 (m, 2H) 1.40 (s, 9H).

Example A-28:6-(2-(Piperidin-4-ylmethoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3,3-dioxide Hydrochloride

A solution of tert-butyl4-(((5-(3,3-dioxido-1,3-benzoxathiol-6-yl)-pyrimidin-2-yl]oxy}methyl)piperidine-1-carboxylate(1.66 g, 3.6 mmol) in dioxane (30 mL) was treated with hydrochloric acidsolution (4M) in dioxane (5 mL) and stirred at 70° C. for 24 hours. Uponcooling a precipitate was filtered off to afford title compound (1.3 g,91%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (br. s,1H), 9.03 (s, 2H), 8.76 (br. s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.76 (s,1H), 7.66 (d, J=8.1 Hz, 1H), 5.46 (s, 2H), 4.27 (d, J=6.5 Hz, 2H), 3.29(d, J=12.4 Hz, 2H), 2.90 (m, 2H), 2.12 (m, 1H), 1.89 (d, J=13.2 Hz, 2H),1.55 (m, 2H).

Example A-29:6-(2-((1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)methoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of6-(2-(piperidin-4-ylmethoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (0.6 g, 1.5 mmol) and 2,5-dichloropyrimidine(0.22 g, 0.63 mmol) in aceonitrile (20 mL) was added triethylamine (0.6g, 2 mmol) and the resulting mixture was heated under reflux for 16hours. The volatile compounds were removed under reduced pressure and aresidue was triturated with water (20 mL) to give a solid which wasfiltered off, washed with ether (10 mL) and air-dried to afford thetitle compound (0.24 g, 33.8%) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ 8.74 (s, 2H), 8.24 (s, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.38 (dd,J=8.1, 1.1 Hz, 1H), 7.38 (dd, J=8.1, 1.1 Hz, 1H), 7.27 (s, 2H), 1.39 (m,2H), 5.12 (s, 2H), 4.79 (d, J=13.7 Hz, 2H),), 4.33 (d, J=6.7 Hz, 2H),2.95 (t, J=12.6 Hz, 2H), 2.22 (m, 1H), 1.98 (d, J=11.6 Hz, 2H).

Example A-30: 5-Hydroxybenzo[d][1,3]oxathiol-2-one

To a solution of thiourea (30 g, 0.39 mol) in 2 N aqueous hydrochloricacid (200 mL) was added a solution of quinine (28.4 g, 0.26 mol) inglacial acetic acid (28.4 g, 0.26 mol)). The resulting mixture wasstirred at room temperature for 30 minutes, during which time a mass ofcrystalline thiouronium salt precipitated. Upon heating on a steam bath,the salt was re-dissolved to give a clear solution. The mixture washeated for 1 hour, and then chilled in an ice bath until crystallizationwas complete. The solid precipitate was collected, washed with water,and dried to give the title compound (55 g, 83%) as a white solid. Theproduct was used in the next step without further purification.

Example A-31: 5-Benzyloxybenzo[d][1,3]oxathiol-2-one

A solution of 5-hydroxybenzo[d][1,3]oxathiol-2-one (10 g, 0.06 mol) inacetonitrile (100 mL) was treated with potassium carbonate (16.5 g, 0.12mol) of and benzyl bromide (7.8 mL, 0.07 mol). The reaction mixture wasstirred at 70° C. for 16 hours. Upon cooling to ambient temperature, thesolution was filtered to remove inorganic salts and the filtrate wasconcentrated under reduced pressure to a volume of 150 mL. A precipitatewas formed, filtered off and washed with ether to afford the titleproduct (11.8 g, 77%) as a white powder. The material used in the nextstep without further purification.

Example A-32: 5-Benzyloxybenzo[d][1,3]oxathiole

A mixture of 5-benzyloxybenzo[d][1,3]oxathiol-2-one (11.8 g, 0.046 mol),potassium carbonate (11.8 g, 0.046 mol) and 18-crown-6 (0.2 g, 0.8 mmol)in dibromomethane (100 mL) and water (4 mL) was stirred at reflux underargon for 48 hours. Upon cooling, the inorganic salts were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue after evaporation was treated with dichloromethane (150 mL). Theorganic layer was separated, washed with brine (2×50 mL) and dried overmagnesium sulfate. The solution was filtered and the filtrate wasevaporated under reduced pressure. The residue after evaporation wastreated with dry ether (50 mL) with cooling in dry ice-acetone bath andstarred for 30 minutes. A formed precipitate was filtered off and washedon filter with cold dry ether (20 mL) to afford the title compound (9.0g, 81.5%) as a white powder. The product was used in the next stepwithout further purification.

Example A-33: 5-Benzyloxybenzo[d][1,3]oxathiole 3,3-dioxide

Into solution of 5-benzyloxybenzo[d][1,3]oxathiole (9 g, 0.037 mol) inacetic acid (100 mL) was added hydrogen peroxide (25 mL of 30% watersolution) and the reaction mixture was stirred overnight at 70° C. Uponcooling to ambient temperature the reaction mixture was diluted withwater (100 mL). A formed precipitate was filtered off and washed withwater (2×30 mL) to afford upon drying on air 6.2 g (63%) of5-(benzyloxy)-1,3-benzoxathiole 3,3-dioxide. The product was used in thenext step without further purification.

Example A-34: 5-Hydroxy-2H-benzo[d][1,3]oxathiole 3,3-dioxide

To a mixture of 5-benzyloxybenzo[d][1,3]oxathiole 3,3-dioxide (5.0 g,0.018 mol) and palladium on charcoal (Pd/C, 0.7 g) in 10% mineral oilwas added tetrahydrofuran (70 mL) and stirred under hydrogen at ambientpressure and temperature for 16 hours. The reaction mixture was thenfiltered through a pad of celite and the filtrate was evaporated underreduced pressure. The residue after evaporation was washed with ether(30 mL) to afford the title compound (3.01 g, 89%) as a white solid. Theproduct was used in the next step without further purification.

Example A-35: 3,3-Dioxido-2H-benzo[d][1,3]oxathiol-5-yltrifluoromethanesulfonate

A solution of 5-hydroxy-2H-benzo[d][1,3]oxathiole 3,3-dioxide (3.01 g,0.016 mol) in pyridine (30 mL) at 0° C. was treated with triflicanhydride (5.2 g, 0.019 mol). The reaction mixture was stirred for 40minutes at 0° C. and 16 hours at ambient temperature. The volatiles wereremoved under reduced pressure and the solution was concentrated to givean oil which was treated with ethyl acetate (70 mL). The suspension waswashed with 10% aqueous solution of citric acid (70 mL) followed bybrine (50 mL) and water (50 mL). The organic layer was separated, driedover magnesium sulfate and filtered. The filtrate was evaporated underreduced pressure and the residue after evaporation was subjected tocolumn chromatography elution with dichloromethane to afford the titleproduct (3.4 g, 66%) as a white powder. The product was used in the nextstep without further purification.

Example A-36: (1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)methanol

A solution containing (piperidin-4-yl)methanol (124.6 g, 1.08 mol),2,5-dichloropyrimidine (161.2 g, 1.08 mol) and triethylamine (438 g, 4.3mol) in acetonitrile (1000 mL) was heated under reflux for 16 hours. Thereaction mixture was allowed to cool to room temperature and filtered.The solid was washed with ether (300 mL) and dried to afford the titlecompound (203.2 g, 82.4%) as a beige powder. ¹H NMR (400 MHz, DMSO-d₆) δ8.36 (s, 2H), 4.58 (d, J=13.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 3.26 (t,J=5.7 Hz, 2H), 2.87 (td, J=12.7, 2.2 Hz, 2H), 1.67 (m, 3H), 1.05 (m,2H).

Example A-37: (1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)methylMethanesulfonate

To a solution of (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)methylmethanesulfonate (203 g, 0.89 mol) and triethylamine (180.4 g, 1.78 mol)in dichloromethane (1500 mL) at 0° C. was added methanesulfonyl chloride(112.3 g, 0.98 mol). The reaction mixture was stirred at ambienttemperature for 4 hours and washed sequentially with 0.1N hydrochloricacid (500 mL) and brine (300 mL). The organic layer was extracted anddried over sodium sulfate, filtered and the filtrate was concentrated invacuo to afford the title product (120.1 g, 88%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.22 (s, 2H), 4.76 (d, J=13.5 Hz, 2H), 4.10 (d,J=6.6 Hz, 2H), 3.02 (s, 3H), 2.90 (td, J=12.9, 2.52 Hz, 2H), 2.06 (m,1H), 1.84 (d, J=12.5 Hz, 2H), 1.30 (m, 2H).

Example A-38:2-(4-((4-Bromo-2-fluorophenoxy)methyl]piperidin-1-yl)-5-chloroPyrimidine

A suspension of (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)methylmethanesulfonate (244.3 g, 0.8 mol), 4-bromo-2-fluorophenol (206.0 g,1.07 mol) and potassium carbonate (331.0 g, 2.4 mol) indimethylsulfoxide (2.5 L) was heated at 110° C. for 16 hours. Aftercooling to room temperature, dimethylsulfoxide was removed under reducedpressure and the resultant residue was treated with water (2.0 L). Asolid precipitated out and was filtered and recrystallized fromisopropanol (1.5 L) to afford the title product (246.1 g, 77%) as awhite crystalline powder: ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 2H), 7.24(dd, J=10.5, 2.3 Hz, 1H), 7.18 (dt, J=8.7, 1.9 Hz, 1H), 6.83 (t, J=8.8Hz, 1H), 4.77 (d, J=13.4 Hz, 2H), 3.87 (d, J=6.5 Hz, 2H),), 2.94 (td,J=12.9, 2.6 Hz, 2H), 2.14 (m, 1H), 1.93 (d, J=12.4 Hz, 2H), 1.34 (qd,J=12.5, 4.28 Hz, 2H).

Example A-39:5-Chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine

A mixture of2-(4-((4-bromo-2-fluorophenoxy)methyl)piperidin-1-yl)-5-chloropyrimidine(246.0 g, 0.6 mol),4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane (187.0 g,0.746 mol), 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (22.5 g, 0.05 mol) and potassium acetate (241.0 g, 2.45 mol)in acetonitrile (2.5 L) was stirred under argon at 70° C. for 16 hours.The reaction mixture was cooled to room temperature and diluted withethyl acetate (2.0 L) and washed with brine (1.0 L). The organic phasewas separated, dried over magnesium sulfate, filtered and the filtratewas evaporated under reduced pressure. The residue was purified bycolumn chromatography eluting with hexanes-ethyl acetate mixture 10:1 byvolume to afford the title product (234.8 g, 85.4%) as a white powder.¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 7.42 (d, J=8.2 Hz, 1H), 7.31(d, J=11.74, 1.85 Hz, 1H), 1.27 (s, 12H), 7.15 (t, J=8.2 Hz, 1H), 4.61(d, J=13.5 Hz, 2H), 3.96 (d, J=6.5 Hz, 2H), 2.94 (t, J=14.0 Hz, 2H),2.06 (m, 1H), 1.82 (d, J=13.5 Hz, 2H).

Example A-40:5-(4-((1-5-Chloropyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

A mixture of5-chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine(1.0 g, 3.1 mmol), 3,3-dioxido-2H-benzo[d][1,3]oxathiol-5-yltrifluoromethanesulfonate (1.4 g, 3.1 mmol), potassium carbonate (1.28g, 9.3 mmol) and 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium(II) Pd(dppf)Cl₂ (0.15 g, 0.2 mmol) in (1:1) water-dioxane mixture (34mL) was stirred under argon at ambient temperature for 1 hour. Thesolution was filtered and the solid was purified by columnchromatography on silica gel eluting with dichloromethane to affordcrude product. This material was dissolved in dioxane (20 mL) andstirred with Lewatit® MonoPlus SP-112 resin (0.5 g) for 2 hour. Themixture was filtered and the filtrate was evaporated in vacuo to affordthe title product (0.15 g, 10%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.39 (s, 1H), 1.27 (m, 2H), 7.98 (dd, J=8.8, 1.84, 1H), 7.65(dd, J=12.8, 2.0, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.22 (t, J=8.9, 1H), 5.44(s, 2H), 4.62 (d, J=13.3 Hz, 2H), 3.99 (d, J=6.4 Hz, 2H), 2.97 (t,J=12.7 Hz, 2H), 2.12 (m, 1H), 1.84 (d, J=13.1 Hz, 2H).

Example A-41:6-(4-((1-(4-Chloro-1,3,5-triazin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

A suspension6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[1,3]oxathiole3,3-dioxide hydrochloride (500 mg, 1.2 mmol),2,4-dichloro-1,3,5-triazine (217 mg, 1.4 mmol) and triethylamine (390mg, 3.0 mmol) in acetonitrile (20 mL) was heated under reflux for 16hours. The volatiles were removed under reduced pressure and the residuewas triturated with water (20 mL). A solid precipitate was filtered off,washed with cold methanol (10 mL) of MeOH and dried to afford the titleproduct (540 mg, 91%) as a white solid. The material was used in thenext step without further purification.

Example A-42:6-(4-((1-(1,3,5-Triazin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

A mixture of6-(4-((1-(4-chloro-1,3,5-triazin-2-yl)piperidin-4-yl)methoxy)-3-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide (500 mg, 1.0 mmol) and 10% palladium over charcoal (Pd/C, 11mg) in THF (150 mL) was stirred under hydrogen at ambient temperatureand pressure for 16 hours. The reaction mixture was filtered through apad of celite and the solvents were evaporated to give an oil which wastriturated with methanol (50 mL) to form a precipitate. This precipitatewas filtered off and dried to afford the title compound (396 mg, 85%) asa white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 2H), 7.89 (d, J=8.9Hz, 1H), 5.43 (s, 2H), 7.72 (d, J=12.8 Hz, 1H), 7.55-7.64 (m, 3H),1.18-1.34 (m, 2H), 7.29 (t, J=8.9 Hz, 1H), 1.90 (d, J=13.2 Hz, 2H)2.11-2.24 (m, 1H), 3.01 (t, J=13.2 Hz, 2H), 4.02 (d, J=6.6 Hz, 2H), 4.71(d, J=13.2 Hz, 2H).

Example A-43: tert-Butyl3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate

To a stirring solution containing tert-butyl3-(hydroxymethyl)azetidine-1-carboxylate (5.0 g, 26.7 mmol) andtriethylamine (7.4 mL, 53.4 mmol) in dichloromethane (50.0 mL) at 0° C.was added methanesulfonyl chloride (2.3 mL, 29.4 mmol). The reactionmixture was stirred at ambient temperature for 4 hours and washedsequentially with 0.1N hydrochloric acid (30 mL) and brine (30 mL). Theorganic layer collected, dried over Na₂SO₄ and concentrated in vacuo toafford the title compound (6.6 g, 93%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 4.34 (d, J=6.7 Hz, 1H), 3.86-3.96 (m, 2H), 3.57-3.67 (m,2H), 3.21 (s, 1H), 2.84-2.96 (m, 1H), 1.38 (s, 9H).

Example A-44: Tert-Butyl3-((4-bromo-2-fluorophenoxy)methyl)azetidine-1-carboxylate

A suspension of tert-butyl3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (6.6 g, 24.9mmol), 4-bromo-2-fluorophenol (5.7 g, 29.9 mmol) and potassium carbonate(6.9 g, 49.8 mmol) in dimethylsulfoxide (100 mL) was stirred at 110° C.for 16 hours. Upon cooling to room temperature, dimethylsulfoxide wasremoved in vacuo and the residue was triturated with water (100 mL). Asolid precipitate was formed, filtered off and dried to afford the titlecompound (7.9 g, 88%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ7.54 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 7.17 (t, J=8.9 Hz, 1H),4.18 (d, J=6.7 Hz, 1H), 3.87-4.03 (m, 2H), 3.61-3.75 (m, 2H), 2.89-3.02(m, 1H), 1.38 (s, 9H).

Example A-45: Tert-Butyl3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)azetidine-1-carboxylate

A mixture of tert-butyl3-((4-bromo-2-fluorophenoxy)methyl)azetidine-1-carboxylate (7.9 g, 21.9mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane (6.7g, 26.3 mmol), (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (0.64 g, 0.85 mmol) and potassium acetate in acetonitrile(100 mL) was stirred under argon at 70° C. for 16 hours. Upon completionthe reaction mixture was diluted with ethyl acetate (100 mL) and washedwith brine (100 mL). The organic phase was separated, dried overmagnesium sulfate, filtered and the filtrate was evaporated underreduced pressure to afford the title compound (8.9 g, 100%) as a whitepowder. The product was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (d, J=8.9 Hz, 1H), 7.32(d, J=8.9 Hz, 1H), 7.19 (t, J=8.9 Hz, 1H), 4.20 (d, J=6.7 Hz, 1H),3.88-4.03 (m, 2H), 3.59-3.76 (m, 2H), 2.90-3.04 (m, 1H), 1.37 (s, 9H),1.15 (s, 12H).

Example A-46: Tert-butyl3-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)azetidine-1-carboxylate

A solution containing tert-butyl3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)azetidine-1-carboxylate(8.9 g, 21.9 mmol), 3,3-dioxido-2H-benzo[d][1,3]oxathiol-5-yltrifluoromethanesulfonate (6.95 g, 21.9 mmol), potassium carbonate (18.1g, 131.4 mmol) and (bisdiphenylphosphino)ferrocene dichloropalladium(II) Pd(dppf)Cl₂ (0.8 g, 1.1 mmol) in a 1:1 water-dioxane mixture (260mL) was stirred under argon at ambient temperature for 1 hour. Aprecipitate was formed, filtered and was purified by columnchromatography on silica gel eluting with dichloromethane to afford anoil. This material was dissolved in dioxane (50 mL) and stirred withwith Lewatit® MonoPlus SP-112 resin (1.2 g) for 2 hours. The reactionmixture was then filtered and the solvent was removed under reducedpressure to afford the title compound (2.6 g, 26%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=8.9 Hz, 1H), 7.73 (d, J=12.8 Hz,1H), 7.56-7.64 (m, 3H), 7.31 (t, J=8.9 Hz, 1H), 5.44 (s, 2H), 4.26 (d,J=6.7 Hz, 1H), 3.88-4.05 (m, 2H), 3.62-3.78 (m, 2H), 2.92-3.06 (m, 1H),1.38 (s, 9H).

Example A-47:6-(4-(Azetidin-3-ylmethoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide Hydrochloride

A solution of tert-butyl3-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)azetidine-1-carboxylate(1.2 g, 2.3 mmol) in dioxane (15 mL) was treated with 4M hydrochloricacid solution in dioxane (3 mL) and stirred at 70° C. for 24 hours.After cooling to room temperature, a solid was formed which was filteredto afford the title compound (1.0 g, 97%) as a white powder. ¹H NMR (400MHz, DMSO-d₆) δ 8.25 (br.s, 2H), 7.90 (d, J=8.9 Hz, 1H), 7.76 (d, J=12.8Hz, 1H), 7.56-7.68 (m, 3H), 7.33 (t, J=8.9 Hz, 1H), 5.44 (s, 2H), 4.33(d, J=6.7 Hz, 1H), 4.01-4.12 (m, 2H), 3.80-3.91 (m, 2H), 3.19-3.30 (m,1H).

Example A-48:6-(4-((1-(5-Chloropyrimidin-2-yl)azetidin-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of6-(4-(azetidin-3-ylmethoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (200 mg, 0.52 mmol) and 2,5-dichloropyrimidine(93 mg, 0.63 mmol) in acetonitrile (10 mL) was added triethylamine (209mg, 2.08 mmol) and the resulting mixture was heated under refluxovernight. The volatiles were evaporated under reduced pressure and theresidue was triturated with water (20 mL). A solid precipitate wasfiltered off, washed with methanol (10 mL) and dried to afford the titlecompound (63 mg, 26%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ8.41 (s, 2H). 3.12-3.25 (m, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.72 (d, J=12.8Hz, 1H), 7.54-7.66 (m, 3H), 7.33 (t, J=8.9 Hz, 1H), 5.43 (s, 2H), 4.36(d, J=6.7 Hz, 1H), 4.15-4.26 (m, 2H), 3.86-3.99 (m, 2H).

Example A-49: 3-Isopropyl-5-(trichloromethyl)-1,2,4-oxadiazole

A solution of N-hydroxyisobutyramidine (7 g, 48 mmol), trichloroaceticanhydride (42 g, 137 mmol) in toluene (40 mL) was refluxed for 1 hour.The reaction was quenched with water (200 mL) and the resultant mixturewas extracted with dichloromethane (2×150 mL). The combined organiclayers were dried, filtered, and concentrated to afford the titlecompound (15.7 g, 100%). The product was used in the next step withoutfurther purification

Example A-50: 3-Isopropyl-1,2,4-oxadiazol-5-ol

A solution of 3-isopropyl-5-(trichloromethyl)-1,2,4-oxadiazole (50 g,219 mmol) and potassium hydroxide (24.0 g, 428 mmol) in ethanol (300 mL)was stirred at 80° C. for 10 minutes. The reaction mixture was thenconcentrated and diluted with water (500 mL) and the pH value wasadjusted to 5 with 33% hydrochloric acid. The aqueous layer wasextracted with ethyl acetate (2×300 mL) and the combined organicextracts were dried over magnesium sulfate, filtered, and the filtratewas evaporated to afford crude product. The crude product wasre-crystallized from ethyl acetate-hexanes mixture (250 mL, 1:10 byvolume) to afford the title compound (24.0 g, 87%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 12.18 (br.s, 1H), 2.76-2.90 (m, 1H), 1.18 (d,J=7.0 Hz, 6H).

Example A-51: 5-Chloro-3-isopropyl-1,2,4-oxadiazole

A solution of 3-isopropyl-1,2,4-oxadiazol-5-ol (300 mg, 2.23 mmol),phosphoryl chloride (1.02 g, 6.71 mmol) in pyridine (10 mL) was heatedto 100° C. for 1 hour. The reaction was then quenched with water (50 mL)and the aqueous phase was extracted with EtOAc (2×50 mL). The organiclayers were combined, dried over magnesium sulfate, filtered and thefiltrate was concentrated to afford the title compound (103 mg, 30%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (d, J=7.0 Hz, 6H),3.05-3.19 (m, 1H).

Example A-52:6-(3-Fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)azetidin-3-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of of6-(4-(azetidin-3-ylmethoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (300 mg, 0.78 mmol) and5-chloro-3-isopropyl-1,2,4-oxadiazole (171 mg, 1.17 mmol) inacetonitrile (10 mL) was added triethylamine (157 mg, 1.56 mmol) and theresulting mixture was heated under reflux for 16 hours. The volatileswere evaporated under reduced pressure and the residue was trituratedwith water (20 mL). A precipitate was filtered off, washed with coldmethanol (10 mL) and dried to afford the title compound (28 mg, 8%) as awhite powder. ¹H NMR (400 MHz, DMSO-d₆) δ 1.18 (d, J=7.0 Hz, 6H),2.77-2.87 (m, 1H), 3.21-3.30 (m, 1H), 3.99-4.07 (m, 2H), 3.27-4.34 (m,2H), 4.35 (d, J=6.7 Hz, 1H), 5.44 (s, 2H), 7.32 (t, J=8.9 Hz, 1H),7.56-7.65 (m, 3H), 7.73 (d, J=12.8 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H)

Example A-53: Ethyl 2-chloro-3-oxopropanoate

To a solution of ethyl chloroacetate (50.0 g, 0.409 mol) and ethylformate (30.3 g, 0.409 mol) in toluene (500 mL) at 0° C. was addedsodium ethoxide (33.0 g, 0.49 mol). The reaction mixture was stirred at0° C. for 5 hours and then at ambient temperature for 12 hours. Thereaction mixture was quenched with water (250 mL), and extracted withether (2×250 mL). The aqueous layer was cooled to 0° C. and acidified topH 4 with 5N hydrochloric acid solution. The aqueous layer was thenextracted with ether (3×300 mL) and the combined organic extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure to furnish the title compound (20.0 g, 19%) as a light brownoil. The compound was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 1.21 (t, J=7.1 Hz, 3H), 4.14(q, J=7.1 Hz, 2H), 7.94 (s, 1H), 11.74 (br.s, 1H).

Example A-54: Tert-Butyl4-(5-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate

A mixture of tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate(1.0 g, 8.2 mmol) and ethyl 2-chloro-3-oxopropanoate (2.5 g, 16.4 mmol)in toluene (40 mL) was heated at 90° C. for 2 hours. The reactionmixture was cooled and partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate (200 mL, 1:1 by volume). The organics werewashed with water (50 mL) and brine (50 mL). The organic extract wasdried over sodium sulfate, filtered and the filtrate was evaporated. Theoily residue after evaporation was subjected to column chromatography onsilica gel eluting with 3:7 by volume mixture ethyl acetate-hexanesmixture to afford the title compound (2.0 g, 72%) as an yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ 1.28 (t, J=7.1 Hz, 3H), 1.40 (s, 9H), 1.49-1.62(m, 2H), 2.03 (d, J=13.2 Hz, 2H), 2.80-2.99 (m, 2H), 3.21-3.30 (m, 1H),4.00 (d, J=13.2 Hz, 2H), 8.33 (s, 1H)

Example A-55: tert-Butyl4-(5-(hydroxymethyl)-1,3-thiazol-2-yl)piperidine-1-carboxylate

A solution of tert-butyl4-(5-(ethoxycarbonyl)-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.70 g;6.58 mmol) in tetrahydrofuran (30 mL) at 0° C. was treated with 1Msolution of lithium aluminum hydride in tetrahydrofuran (7.60 mL, 7.60mmol). The reaction mixture was stirred at room temperature for 1 hour,then was cooled to 0° C. and carefully quenched with water (0.76 mL).After stirring for 10 minutes, a solution of aqueous solution sodiumhydroxide (5N, 0.38 mL) was added and was stirred again for another 10minutes and filtered through a pad of celite. The filtrate wasconcentrated in vacuo to afford the title compound (0.8 g, 46%) as awhite solid which was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (s, 1H), 5.46 (t, J=5.7Hz, 2H), 4.62 (d, J=5.7 Hz, 2H), 3.99 (d, J=13.2 Hz, 2H), 3.09-3.20 (m,1H), 2.79-2.99 (m, 2H), 1.45-1.58 (m, 2H), 1.99 (d, J=13.2 Hz, 2H), 1.40(s, 9H).

Example A-56: Tert-Butyl4-(5-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)thiazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(5-(hydroxymethyl)-1,3-thiazol-2-yl)piperidine-1-carboxylate (233 mg,0.78 mmol), 4-(3,3-dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenol (219mg, 0.78 mmol), triphenylphosphine (225 mg, 0.85 mmol) intetrahydrofuran (10 mL) at 0° C. was added dropwise diisopropylazodicarboxylate (174 mg, 0.85 mmol) and the reaction mixture wasstirred at ambient temperature for 24 hours. Water (40 mL) was thenadded and the reaction mixture was extracted with ethyl acetate (50 mL).The organic layer was washed with 1M aqueous solution potassiumhydroxide (20 mL), brine (20 mL) and dried over Na₂SO₄ and filtered. Thefiltrate was evaporated to give an oil which was purified by columnchromatography on silica gel eluting with 10:1 mixture by volumechloroform-tetrahydrofuran to afford the title compound (410 mg, 67%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J=8.9 Hz, 1H), 1.40(s, 9H), 7.83 (s, 1H), 7.74 (d, J=12.8 Hz, 1H), 7.56-7.67 (m, 3H), 7.44(t, J=8.9 Hz, 1H), 5.48 (s, 2H), 5.43 (s, 2H), 3.99 (d, J=13.2 Hz, 2H),3.14-3.24 (m, 1H), 2.79-2.98 (m, 2H), 2.01 (d, J=13.2 Hz, 2H), 1.47-1.61(m, 2H).

Example A-57:6-(3-Fluoro-4-((2-piperidin-4-yl)thiazol-5-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole-3,3-dioxide

A solution of tert-butyl4-(5-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)thiazol-2-yl)piperidine-1-carboxylate (0.41 g, 0.73 mmol)in dioxane (10 mL) was treated with 4M solution of hydrochloric acid indioxane (1 mL) and stirred at 70° C. for 24 hours. A was filtered anddried to afford the title compound (0.26 g, 72%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 9.07 (br s, 1H), 8.89 (brs, 1H), 7.90 (d, J=8.9Hz, 1H), 7.86 (s, 1H), 7.74 (d, J=12.8 Hz, 1H), 7.56-7.65 (m, 3H),7.56-7.65 (m, 3H), 7.45 (t, J=8.9 Hz, 1H), 5.50 (s, 2H), 5.44 (s, 2H),3.27-3.40 (m, 3H), 2.94-3.07 (m, 2H), 2.18 (d, J=13.2 Hz, 2H), 1.85-1.99(m, 2H).

Example A-58:6-(4-((2-(1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)thiazol-5-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole-3,3-dioxide

To a suspension of6-(3-fluoro-4-((2-piperidin-4-yl)thiazol-5-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole-3,3-dioxidehydrochloride (130 mg, 0.26 mmol) and 2,5-dichloropyrimidine (43 mg,0.29 mmol) in acetonitrile (10 mL) was added triethylamine (66 mg, 0.65mmol) and the reaction mixture was heated under reflux for 16 hours. Thereaction mixture was then cooled and filtered to give a solid which waswashed with ether (10 mL) and dried to afford the title compound (96 mg,64%) as a beige powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H), 7.89(d, J=8.9 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J=12.8 Hz, 1H), 7.55-7.65 (m,3H), 7.44 (t, J=8.9 Hz, 1H), 5.48 (s, 2H), 5.44 (s, 2H), 4.63 (d, J=13.2Hz, 2H), 3.27-3.41 (m, 1H), 3.11 (t, J=13.2 Hz, 2H), 2.11 (d, J=13.2 Hz,2H), 1.56-1.70 (m, 2H).

Example A-59:6-(3-Fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methoxy) phenyl)-2H-benzo[d][1,3]oxathiole 3,3-dioxide

To a suspension of6-((3-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[1,3]oxathiole3,3-dioxide hydrochloride (145 mg, 0.35 mmol) and5-chloro-3-isopropyl-1,2,4-oxadiazole (103 mg, 0.70 mmol) inacetonitrile (10 mL) was added triethylamine (124 mg, 1.22 mmol) and thereaction mixture was heated under reflux for 16 hours. After cooling,the reaction mixture was concentrated under reduced pressure and theresidue was triturated with water (20 mL). A solid precipitate wasfiltered off, washed with cold methanol (10 mL) and dried to afford thetitle compound (41 mg, 24%) as a beige powder. ¹H NMR (400 MHz, DMSO-d₆)δ 7.89 (d, J=8.9 Hz, 1H), 7.72 (d, J=12.8 Hz, 1H), 7.54-7.64 (m, 3H),7.29 (t, J=8.9 Hz, 1H), 5.43 (s, 2H), 4.01 (d, J=13.2 Hz, 2H), 4.03 (d,J=6.6 Hz, 2H), 3.15 (t, J=13.2 Hz, 2H), 2.74-2.88 (m, 1H), 2.01-2.16 (m,1H), 1.88 (d, J=13.2 Hz, 2H), 1.29-1.43 (m, 2H), 1.19 (d, J=7.0 Hz, 6H).

Example A-60:2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a solution of 4-bromo-2-fluorophenol (5.0 g, 26.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (7.97 g, 31.4mmol) and (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (1.32 g, 1.8 mmol) in acetonitrile (200 mL) was addedpotassium acetate (10.3 g, 104.8 mmol) and the resulting mixture wasstirred at 67° C. for 16 hours. After cooling to room temperature, thereaction mixture was filtered through celite and the filtrate wasevaporated. The residue after evaporation was treated with water (300mL) and the mixture was extracted with ethyl acetate (3×150 mL). Thecombined extracts were washed with brine (50 mL), dried over Na₂SO₄,filtered and the filtrate was evaporated. The residue after evaporationwas taken up in hexanes (150 mL) and the resulting mixture was heated atreflux for 1 hour and the solution was filtered hot and the filtrate wasevaporated to dryness to afford the title compound (5.8 g, 93%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.55 (m, 2H), 6.99 (t, J=8.8Hz, 1H), 5.79 (br.s, 1H), 1.34 (s, 12H),

Example A-61: 6-(3-Fluoro-4-hydroxyphenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of 3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (1.0 g, 3.1 mmol),2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.1 g,4.6 mmol), 2M aqueous (4.7 mL, 9.3 mmol) solution in toluene (50 mL) wasadded (bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂(150 mg, 0.2 mmol) under argon and the reaction mixture was stirred at80° C. for 3 hours. Upon completion, the reaction was quenched withwater (20 mL) and the reaction mixture was extracted with ethyl acetate(3×50 mL). The combined extracts were dried over magnesium sulfate,filtered and the filtrate was evaporated to give an oil which waspurified by column chromatography eluting with hexane-ethyl acetatemixture (gradient 4:1-2:1) to afford the title compound (300 mg, 35%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (br.s, 1H), 7.86 (d,J=8.4 Hz, 1H), 7.6-7.67 (m, 1H), 7.51-7.59 (m, 2H), 7.41-7.48 (m, 1H),7.05 (t, J=8.8 Hz, 1H), 5.42 (s, 2H).

Example A-62:4-(3,3-Dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyl TrifluoroMethanesulfonate

To a suspension of6-(3-fluoro-4-hydroxyphenyl)-2H-benzo[d][1,3]oxathiole 3,3-dioxide (1.0g, 3.57 mmol) in pyridine (6 mL) at 0° C. was added dropwise triflicanhydride (1.1 g, 3.92 mmol). The mixture was stirred at ambienttemperature for 17 hours and then the reaction mixture was diluted withethyl acetate (40 mL) and washed with 10% aqueous solution citric acid(40 mL), water (40 mL), brine (50 mL), dried over Na₂SO₄, and filtered.The filtrate was evaporated under reduced pressure and the residual oilwas sonicated with ether (10 mL) to form precipitate which was filtered,and dried to afford the title compound (1.05 g, 71%) as a white solid. HNMR (400 MHz, DMSO-d₆) δ 8.05-8.11 (m, 1H). 7.99 (d, J=8.2 Hz, 1H),7.72-7.88 (m, 3H), 7.66 (d, J=8.0 Hz, 1H), 5.47 (s, 2H).

Example A-63: Tert-Butyl4-[4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyl)Piperazine-1-carboxylate

A mixture of4-(3,3-Dioxido-2H-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyl trifluoromethanesulfonate (515 mg, 1.25 mmol), tert-butyl 1-piperazinecarboxylate(279 mg, 1.5 mmol), cesium carbonate (610 mg, 1.87 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 93 mg, 0.14 mmol),palladium acetate (23 mg, 0.1 mmol) in toluene (15 mL) was stirred underargon at 100° C. for 16 hours. The reaction mixture was cooled toambient temperature and quenched with water (10 mL) and extracted withethyl acetate (3×30 mL). The combined extracts were washed with brine(30 mL), dried over Na₂SO₄, filtered and the filtrate was concentratedin vacuo to give an oil. This oil was purified by column chromatographyeluting with hexanes-ethyl acetate mixture, gradient (5:1-3:1) to affordthe title compound (350 mg, 63%) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ 7.88 (d, J=8.0 Hz, 1H), 7.53-7.69 (m, 4H), 7.14 (t, J=8.8 Hz,1H), 5.43 (s, 2H), 3.45-3.53 (m, 4H), 3.0-3.08 (m, 4H), 1.43 (s, 9H).

Example A-64:6-(3-Fluoro-4-(piperazine-1-yl)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a solution of tert-butyl4-(4-(3,3-dioxido-2-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyl)piperazine-1-carboxylate(250 mg, 0.56 mmol) in dichloromethane (30 mL) was added trifluoroaceticacid (15 mL) and the mixture was stirred at ambient temperature for 20minutes and then evaporated to dryness to afford the title compound (190mg, 97%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 7.84-7.91 (m,1H), 7.51-7.66 (m, 4H), 7.05-7.14 (m, 1H), 5.42 (s, 2H), 2.97-3.03 (m,4H), 2.81-2.88 (m, 4H).

Example A-65:6-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-fluorophenyl-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of6-(3-fluoro-4-(piperazine-1-yl)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide (200 mg, 0.57 mmol) and 2,5-dichloropyrimidine (94.1 mg,0.63 mmol) in acetonitrile (30 mL) was added triethylamine (116 mg, 1.14mmol) and the reaction mixture was heated to reflux for 16 hours. Uponcompletion, the volatiles were evaporated and the residue was washedwith water (50 mL). To the residue after washing was added acetone (15mL) and the solution was heated at reflux for 30 minutes, stirred atambient temperature for 20 minutes to furnish a solid which was filteredand dried to afford the title compound (80 mg, 30%) as a white powder.¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 2H), 7.88 (d, J=8.3 Hz, 1H), 7.88(d, J=8.3 Hz, 1H), 7.52-7.72 (m, 4H), 7.16 (t, J=9.4 Hz, 1H), 5.43 (s,2H), 3.85-3.95 (m, 4H), 3.11-3.21 (m, 4H).

Example A-66:6-(3-Fluoro-4-(1-(5-isopropylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of6-(3-fluoro-4(piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide (230 mg, 0.57 mmol) and 2-chloro-5-isopropylpyrimidine (94.1mg, 0.63 mmol) in acetonitrile (50 mL) was added triethylamine (230 mg,2.3 mmol) and the reaction mixture was heated to reflux for 6 hours.Upon completion, the reaction mixture was cooled to ambient temperature.A white precipitate was formed which was filtered which was filteredoff, washed with cold water and hexanes and then purified by columnchromatography on silica gel, eluting with dichloromethane-ether mixture(1:1) to give the title compound (190 mg, 67%) as a white powder. ¹H NMR(400 MHz, DMSO-d₆) δ 8.27 (s, 2H), 7.88 (d, J=8.3 Hz, 1H), 7.88 (d,J=8.2 Hz, 1H), 7.71 (d, J=12.8 Hz, 1H) 7.64-7.55 (m, 3H), 7.29 (t, J=8.7Hz, 1H), 5.44 (s, 2H), 5.44 (s, 2H), 4.67 (d, J=12.6 Hz, 2H), 4.02 (d,J=6.4 Hz, 2H), 2.89 (J=12.1 Hz, 2H), 2.79-2.72 (m, 1H), 2.10 (bs, 1H),1.83 (d, J=12.6 Hz, 2H), 1.30-1.19 (m, 2H), 1.18 (d, J=6.8 Hz, 6H).

Example A-67:6-(3-Fluoro-4-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl-2H-benzo[d][1,3]oxathiole 3,3-dioxide

To a suspension of6-(3-fluoro-4-(piperidin-4-yl)phenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide (290 mg, 0.7 mmol) and 2-chloro-5-methoxypyrimidine (115 mg,0.85 mmol) in acetonitrile (20 mL) was added triethylamine (63 mg, 0.6mmol) and the reaction mixture was heated to reflux for 6 hours. Uponcompletion, the reaction mixture was cooled to ambient temperature. Awhite precipitate was formed which was filtered which was filtered off,washed with cold water and hexanes and then the crude product waspurified by column chromatography on silica gel, eluting withdichloromethane to give the title compound (76 mg, 22%) as a whitepowder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.39 (s, 1H), 8.16 (d,J=1.8 Hz, 1H), 7.98 (d, J=8.82 Hz, 1H), 7.65 (d, J=12.8 Hz, 1H), 7.36(d, J=8.8 Hz, 1H) 7.21 (t, J=8.93 Hz, 1H), 5.45 (s, 2H), 4.62 (d,J=13.23 Hz, 2H), 3.99 (d, J=6.36 Hz, 2H), 3.76 (s, 3H), 2.97 (t, J=12.71Hz, 2H), 2.12 (m, 1H), 1.84 (d, J=13.08 Hz, 2H), 1.27 (m, 2H).

Example A-68: (R)-1-(5-Ethylpyrimidin-2-yl)pyrrolidin-2-yl)methanol

To a mixture of (R)-pyrrolidin-2-ylmethanol (1.0 g, 9.9 mmol),2-chloro-5-ethylpyrimidine (2.8 g, 19.8 mmol) and diisopropylethylamine(4.2 g, 32.7 mmol) was added copper iodide CuI (60 mg, 0.3 mmol) and themixture was stirred at ambient temperature for 5 minutes. The reactionmixture was then heated in a conventional CEM microwave system at 80° C.for 20 hours. Upon completion, the reaction mixture was cooled and water(50 mL) was carefully added followed by the addition of a 5% aqueoussolution of citric acid until pH-6-7. A solution of brine was added andthe organic layer was extracted with ethyl acetate (3×100 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and the filtratewas evaporated in vacuo to give an oily residue which was purified bycolumn chromatography eluting with hexanes: ethyl acetate gradientmixture (4:1 to 1:1) to give the title product as a colorless oil (1.3g, 63%). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 2H), 6.2 (br.s, 1H),4.29-4.17 (m, 1H), 3.84-3.51 (m, 4H), 2.47 (q, J=7.6 Hz, 2H), 2.21-2.07(m, 1H), 2.06-1.84 (m, 2H), 1.77-1.65 (m, 1H), 1.19 (t, J=7.6 Hz, 3H).

Example A-69:(R)-2-(2-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidine-1-yl)-5-ethylpurimidine

To a solution of (R)-1-(5-ethylpyrimidin-2-yl)pyrrolidin-2-yl]methanol(1.3 g, 6.3 mmol), 4-bromo-2-fluorophenol (1.2 g, 6.3 mmol),triphenylphosphine (3.3 g, 12.6 mmol) in tetrahydrofuran (40 mL) wasadded diethyl azodicarboxylate (2.6 g, 12.6 mmol) dropwise at 0° C. andthe reaction mixture was stirred at ambient temperature overnight. Uponcompletion, the solvents were then evaporated to dryness and to theresidue was extracted with ethyl acetate (200 mL). The organic layer waswashed with saturated solution of NaHCO₃, brine, dried over Na₂SO₄ andfiltered. The filtrate was evaporated to dryness to give a crude productwhich was purified by column chromatography on silica gel eluting withhexanes: ethyl acetate mixture (1:1) to afford the title compound as awhite solid (1.1 g, 46%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 2H),7.54-7.46 (m, 1H), 7.36-7.28 (m, 2H), 4.41-4.32 (m, 1H), 4.29-4.21 (m,1H), 4.02 (t, J=9.2 Hz, 1H), 3.59-3.5 (m, 1H), 3.46-3.36 (m, 1H),2.47-2.38 (q, J=7.6 Hz, 2H), 2.14-1.89 (m, 4H), 1.13 (t, J=7.6 Hz, 3H).

Example A-70:(R)-5-Ethyl-2-(2-((2-fluoro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidine-1-yl)pyrimidine

To a solution of(R)-2-(2-((4-bromo-2-fluorophenoxy)methyl)pyrrolidine-1-yl)-5-ethylpurimidine(1.1 g, 2.9 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.89 g, 3.5mmol), (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (150 mg, 0.2 mmol) in 1,4-dioxane (40 mL) was addedpotassium acetate (1.2 g, 11.6 mmol) and the resulting mixture wasstirred and heated to 90° C. overnight. Upon cooling, the reactionmixture was poured into a 1:1 mixture of ethyl acetate (100 mL) andwater (100 mL). The solution was filtered through a pad of celite (1 cmin length) and the organic layer was washed with water, brine, driedover Na₂SO₄ and evaporated in vacuo to dryness. To the residue was addedhexanes (50 mL) and the resultant solution was heated to reflux and thenfiltered while keeping it hot. The precipitate formed upon cooling wasfiltered off and purified by column chromatography on silica gel elutingwith hexanes: ethyl acetate to afford the title compound as colorlessoil (1.0 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 2H), 7.56-7.43 (m,2H), 7.23 (t, J=8.3 Hz, 1H), 4.59-4.50 (m, 1H), 4.45-4.37 (m, 1H), 4.03(t, J=8.3 Hz, 1H), 3.77-3.65 (m, 1H), 3.58-3.47 (m, 1H), 2.48 (q, J=7.6Hz, 2H), 2.30-1.97 (m, 4H), 1.34 (s, 12H), 1.21 (t, J=7.6 Hz, 3H).

Example A-71.(R)-6-(4-((1-(5-Ethylpyrimidin-2-yl)pyrrolidin-2-yl)methoxy)-3-fluorophenyl-2H-benzo[d]oxathiole3,3-dioxide

To a solution of(R)-5-ethyl-2-(2-((2-fluoro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidine-1-yl)pyrimidine(470 mg, 1.1 mmol) in dioxane (20 mL) was added3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (350mg, 1.1 mmol), a solution of Na₂CO₃ (2M, 1.7 mL) and(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (40mg, 0.06 mmol). The resulting mixture was to 85° C. for 2 hours and thenstirred at ambient temperature overnight. Water (70 mL) was added to thesolution with stirring followed by the addition of ethyl acetate (50 mL)and then the solution was filtered through a pad of celite. The organicsolution was collected and washed with water, brine, dried over Na₂SO₄,filtered and evaporated in vacuo. The residual oil was purified bycolumn chromatography on silica gel eluting with hexanes: ethyl acetatemixture. The crude product obtained was triturated with ether (20 mL)filtered and dried on standing to give the title compound as a whitesolid (280 mg, 54%). ¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 2H), 7.88 (d,J=8.1 Hz, 1H), 7.76-7.68 (m, 1H), 7.64-7.54 (m, 3H), 7.47 (t, J=8.8 Hz,1H), 5.43 (s, 2H), 4.45-4.3 (m, 2H), 4.08 (t, J=8.4 Hz, 1H), 3.62-3.52(m, 1H), 3.48-3.38 (m, 1H), 2.44 (q, J=7.6 Hz, 2H), 2.18-1.9 (m, 4H),1.13 (t, J=7.6 Hz, 3H).

Example A-72:tert-Butyl-4-(((2-chloropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate

A suspension of tert-butyl4-(((trifluoromethylsulfonyl)oxy)piperidine-1-carboxylate (6.2 g, 21.1mmol), 2-chloropyrimidin-5-ol (2.5 g, 19.2 mmol) and potassium carbonate(13.3 g, 96 mmol) in dimethylsulfoxide (100 mL) was stirred at 110° C.for 16 hours. The reaction mixture was cooled to room temperature anddimethylsulfoxide was distilled off under reduced pressure. The residuewas then treated with water (50 mL) and precipitate was formed, filteredoff and purified by column chromatography eluting with hexanes: ethylacetate mixture (3:2) by volume to afford the title compound (2.0 g,31.7%) as a white crystalline powder: 1H NMR (400 MHz, DMSO-d6) δ 8.53(s, 2H), 4.02 (d, J=6.4 Hz, 2H), 3.96 (d, J=12.4 Hz, 2H), 3.24-3.23 (m,1H), 2.74 (s, 2H), 2.02-1.85 (m, 1H), 1.73 (d, J=11.1 Hz, 2H), 1.39 (s,9H), 1.24-1.02 (m, 2H).

Example A-73:6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d]oxathiole3,3-dioxide

To a mixture of 3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (2.0 g, 6.3 mmol) and4,4,4′,4′,5,5,5′,5′-octanethyl-2,2′-bi-1,3,2-dioxoborolane (1.93 g, 7.6mmol) in acetonitrile (30 mL) were added 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) (Pd(dppf)Cl₂(0.22 g, 0.3 mmol) and potassium acetate (2.5 g, 25 mmol) and thereaction mixture was stirred under argon at 70° C. for 16 hours. Uponcompletion, the reaction mixture was diluted with ethyl acetate (50 mL)and washed with brine (50 mL). The organic layer was collected and driedover magnesium sulfate, filtered and the filtrate was evaporated underreduced pressure. The residue after evaporation was purified by columnchromatography eluting with hexanes: ethyl acetate mixture (10:1) toafford the title compound (0.65 g, 35%) as a white powder. ¹H NMR (400MHz, DMSO-d₆) δ 7.84 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.43 (s,1H), 5.40 (s, 2H), 1.3 (s, 12H).

Example A-74: tert-Butyl4-(((2-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)pyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate

A mixture of of 6-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-2H-benzo[d]oxathiole 3,3-dioxide (0.95 g, 3.2mmol),tert-butyl-4-(((2-chloropyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate(1.05 g, 3.2 mmol), sodium carbonate (2.65 g, 19.2 mmol) and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) (Pd(dppf)Cl₂(0.22 g, 0.3 mmol) in a 1:1 water: dioxane mixture (50 mL) was stirredunder argon at 70° C. for 12 hours. A precipitate was formed, filteredand purified by column chromatography on silica gel eluting withhexanes: ethyl acetate mixture (4:1) to afford the title compound (0.5g, 33.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 2H), 8.20 (d, J=8.2 Hz,1H), 8.05 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 5.47 (s, 2H), 4.11 (d, J=6.4Hz, 2H), 3.98 (d, J=13.3 Hz, 2H), 2.76 (s, 2H), 1.99 (s, 1H), 1.77 (d,J=11.9 Hz, 2H), 1.40 (s, 9H), 1.27-1.10 (m, 2H).

Example A-75:6-(5-(Piperidin-4-ylmethoxy)pyrimidin-2-yl)-2H-benzo[d][1,3]oxathiole3,3-dioxide Hydrochloride

A solution of tert-butyl4-(((2-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)pyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate(0.5 g, 1.1 mmol) in dioxane (30 mL) was treated with 4M hydrogenchloride in dioxane (5 mL) and stirred at 70° C. for 24 hours. Uponcooling a precipitate was filtered off and dried to afford the titleproduct as a white solid (0.29 g, 66.3%).

Example A-76:6-(5-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyrimidin-2-yl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a suspension of6-(5-(piperidin-4-ylmethoxy)pyrimidin-2-yl)-2H-benzo[d][1,3]oxathiole3,3-dioxide hydrochloride (290 mg, 0.7 mmol) and2-chloro-5-ethylpyrimidine (128 mg, 0.7 mmol) in acetonitrile (20 mL)was added triethylamine (210 mg, 2.1 mmol) and the mixture was heatedunder reflux overnight. The solvent was then removed under reducedpressure and the residue was triturated with water (20 mL). A solidprecipitate was formed and filtered off, washed with ether (10 mL) andair-dried to afford the title product (56 mg, 17.1%) as a white powder.¹H NMR (300 MHz, CDCl₃) δ 8.49 (s, 2H), 8.26 (d, J=8.2 Hz, 1H), 8.20 (s,2H), 8.14 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.28 (s, 1H), 5.10 (s, 2H),4.83 (d, J=13.4 Hz, 2H), 4.01 (d, J=6.3 Hz, 2H), 2.94 (t, J=12.8 Hz,2H), 2.48 (q, J=7.8 Hz, 2H), 2.17 (s, 1H), 1.96 (d, J=12.8 Hz, 2H),1.53-1.31 (m, 2H), 1.21 (t, J=7.6 Hz, 3H).

Example A-77: (S)-1-(5-Ethylpyrimidin-2-yl)pyrrolidin-2-yl)methanol

To a mixture of (R)-pyrrolidin-2-ylmethanol (2.0 g, 19.8 mmol),2-chloro-5-ethylpyrimidine (3.7 g, 25.7 mmol) and diisopropylethylamine(7.7 g, 59.4 mmol) was added copper iodide CuI (380 mg, 2.0 mmol) andthe mixture was stirred at ambient temperature for 5 minutes. Thereaction mixture was then heated in a conventional CEM microwave systemat 80° C. for 20 hours. Upon completion, the reaction mixture was cooledand water (50 mL) was carefully added followed by the addition of a 5%aqueous solution of citric acid until pH-6-7. A solution of brine wasadded and the organic layer was extracted with ethyl acetate (3×100 mL).The combined organic layer was dried over Na₂SO₄, filtered and thefiltrate was evaporated in vacuo to give an oily residue which waspurified by column chromatography eluting with hexanes: ethyl acetategradient mixture (4:1 to 1:1) to give the title product as a colorlessoil (1.3 g, 63%). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 2H), 6.2 (br.s,1H), 4.29-4.17 (m, 1H), 3.84-3.51 (m, 4H), 2.47 (q, J=7.6 Hz, 2H),2.21-2.07 (m, 1H), 2.06-1.84 (m, 2H), 1.77-1.65 (m, 1H), 1.19 (t, J=7.6Hz, 3H).

Example A-78:(S)-2-(2-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidine-1-yl)-5-ethylpyrimidine

To a solution of (S)-1-(5-ethylpyrimidin-2-yl)pyrrolidin-2-yl)methanol(1.7 g, 8.2 mmol), 4-bromo-2-fluorophenol (1.7 g, 9.0 mmol),triphenylphosphine (2.4 g, 9.0 mmol) in tetrahydrofuran (40 mL) wasadded diethyl azodicarboxylate (1.8 g, 9.0 mmol) dropwise at 0° C. andthe reaction mixture was stirred at ambient temperature overnight. Uponcompletion, the solvents were then evaporated to dryness and to theresidue was extracted with ethyl acetate (200 mL). The organic layer waswashed with saturated solution of NaHCO₃, brine, dried over Na₂SO₄ andfiltered. The filtrate was evaporated to dryness to give a crude productwhich was purified by column chromatography on silica gel eluting withhexanes: ethyl acetate mixture (1:1) to afford the title compound as awhite solid (420 mg, 13%). H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 2H),7.54-7.46 (m, 1H), 7.36-7.28 (m, 2H), 4.41-4.32 (m, 1H), 4.29-4.21 (m,1H), 4.02 (t, J=9.2 Hz, 1H), 3.59-3.5 (m, 1H), 3.46-3.36 (m, 1H),2.47-2.38 (q, J=7.6 Hz, 2H), 2.14-1.89 (m, 4H), 1.13 (t, J=7.6 Hz, 3H).

Example A-79:(S)-5-Ethyl-2-(2-((2-fluoro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidine-1-yl)pyrimidine

To a solution containing(S)-2-(2-((4-bromo-2-fluorophenoxy)methyl)pyrrolidine-1-yl)-5-ethylpurimidine(420 mg, 1.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (336 mg, 1.3mmol), (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (56 mg, 0.08 mmol) in 1,4-dioxane (40 mL) was addedpotassium acetate (433 mg, 4.4 mmol) and the resulting mixture wasstirred and heated to 90° C. overnight. Upon cooling, the reactionmixture was poured into a 1:1 mixture of ethyl acetate (50 mL) and water(50 mL). The solution was filtered through a pad of celite (1 cm inlength) and the organic layer was washed with water, brine, dried overNa₂SO₄ and evaporated in vacuo to dryness. To the residue was addedhexanes (50 mL) and the resultant solution was heated to reflux and thenfiltered while keeping it hot. The precipitate formed upon cooling wasfiltered off and purified by column chromatography on silica gel elutingwith hexanes: ethyl acetate to afford the title compound as colorlessoil (395 mg, 83%). ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 2H), 7.56-7.43 (m,2H), 7.23 (t, J=8.3 Hz, 1H), 4.59-4.50 (m, 1H), 4.45-4.37 (m, 1H), 4.03(t, J=8.3 Hz, 1H), 3.77-3.65 (m, 1H), 3.58-3.47 (m, 1H), 2.48 (q, J=7.6Hz, 2H), 2.30-1.97 (m, 4H), 1.34 (s, 12H), 1.21 (t, J=7.6 Hz, 3H).

Example A-80:(S)-6-(4-((1-(5-Ethylpyrimidin-2-yl)pyrrolidin-2-yl)methoxy)-3-fluorophenyl-2H-benzo[d]oxathiole3,3-dioxide

To a solution of(5)-5-ethyl-2-(2-((2-fluoro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidine-1-yl)pyrimidine(197 mg, 0.46 mmol) in dioxane (5 mL) was added3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (147mg, 0.46 mmol), a solution of Na₂CO₃ (2M, 0.8 mL) and(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (23mg, 0.03 mmol). The resulting mixture was to 85° C. for 2 hours and thenstirred at ambient temperature overnight. Water (35 mL) was added to thesolution with stirring followed by the addition of ethyl acetate (50 mL)and then the solution was filtered through a pad of celite. The organicsolution was collected and washed with water, brine, dried over Na₂SO₄,filtered and evaporated in vacuo. The residual oil was purified bycolumn chromatography on silica gel eluting with hexanes: ethyl acetatemixture. The crude product obtained was triturated with ether (10 mL)filtered and dried on standing to give the title compound as a whitesolid (92 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 2H), 7.88 (d,J=8.1 Hz, 1H), 7.76-7.68 (m, 1H), 7.64-7.54 (m, 3H), 7.47 (t, J=8.8 Hz,1H), 5.43 (s, 2H), 4.45-4.3 (m, 2H), 4.08 (t, J=8.4 Hz, 1H), 3.62-3.52(m, 1H), 3.48-3.38 (m, 1H), 2.44 (q, J=7.6 Hz, 2H), 2.18-1.9 (m, 4H),1.13 (t, J=7.6 Hz, 3H).

Example A-81:tert-Butyl-(S)-3-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 9.9 mmol) andtriethylamine (2.8 mL, 19.8 mmol) in methylene chloride (50.0 mL) at 0°C. was dropwise added methanesulfonyl chloride (0.85 mL, 10.9 mmol). Thereaction mixture was stirred at ambient temperature for 4 hours and thenwashed sequentially with 0.1 N hydrogen chloride and brine. The organiclayer was dried over Na₂SO₄ filtered, and concentrated in vacuo to yield2.5 g (90%) of the title product as an oil. [M+1]⁺ 280.

Example A-82:tert-Butyl-(S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

Method A: A solution oftert-butyl-(S)-3-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(2.2 g, 7.9 mmol), 4-bromo-2-fluorophenol (1.8 g, 9.5 mmol) andpotassium carbonate (2.2 g, 15.8 mmol) in dimethylformamide (100 mL) wasstirred at 100° C. overnight. After cooling to ambient temperature, thesolvent was removed under reduced pressure. The residue was treated withacetonitrile (100 mL) and the resultant suspension was filtered througha pad of celite. The filtrate was evaporated to dryness and the residuewas treated with water (50 mL). The mixture was extracted with ethylacetate (2×50 mL), dried over sodium sulfate and filtered. The filtratewas evaporated, and purified by chromatography on a silica gel pad (3cm) eluting with a mixture of hexanes: ethyl acetate (4:1) to give thetitle product (2.9 g, 98%) as a light yellow liquid. ¹H-NMR (400 MHz,DMSO-d₆,) δ 7.52 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.16 (t,J=8.7 Hz, 1H), 4.08-3.96 (m, 2H), 3.56-3.06 (m, 4H), 2.75-2.59 (m, 1H),2.09-1.95 (m, 1H), 1.81-1.64 (m, 1H), 1.40 (s, 9H).

Method B: To a solution oftert-butyl-(S)-3-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(8.3 g, 29.7 mmol), 4-bromo-2-fluorophenol (6.8 g, 35.6 mmol) inacetonitrile (200 mL) were added potassium carbonate (12.3 g, 89.1mmol), 18-crown-6 (300 mg) and tetra n-butylammonium bromide (0.48 g,1.5 mmol). The reaction mixture was stirred and heated to refluxovernight. Upon cooling, water (300 mL) and ethyl acetate (300 mL) wereadded. The organic phase was separated, washed with 5% aq. Solution ofpotassium carbonate, brine, dried over Na₂SO₄, filtered and the filtratewas evaporated to dryness. The product was purified by columnchromatography on silica gel eluting with hexanes: ethyl acetate mixtureto afford the title product as a white solid (9.9 g, 89%). ¹H NMR (400MHz, CDCl₃) δ 7.27-7.15 (m, 2H), 6.84 (t, J=8.6 Hz, 1H), 3.96 (d, J=6.7Hz, 2H), 3.66-3.31 (m, 3H), 3.28-3.16 (m, 1H), 2.79-2.63 (m, 1H),2.17-2.02 (m, 1H), 1.89-1.73 (m, 1H), 1.48 (s, 9H).

Example A-83: (S)-3-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidineHydrochloride

To a stirred solution oftert-butyl-(S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate(9.9 g, 26.5 mmol) in dioxane (30 mL) was added 3M solution of hydrogenchloride in dioxane (80 mL) and the mixture was stirred at 40° C.overnight. Upon completion dioxane was evaporated to the residual volumeof 10 mL, and diethyl ether (150 mL) was added. A precipitate wasformed, stirred for 20 minutes then, filtered off and air-dried to givethe title product (8.2 g, 99%). as a white powder. ¹H-NMR (400 MHz,DMSO-d₆,) δ 9.48 (br.s, 2H), 7.52 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.7 Hz,1H), 7.16 (t, J=8.7 Hz, 1H), 4.15-4.03 (m, 2H), 3.40-3.10 (m, 3H),3.03-2.94 (m, 1H), 2.80-2.66 (m, 1H), 2.15-2.02 (m, 1H), 1.81-1.67 (m,1H).

Example A-84:(S)-2-(3-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-5-ethylpyrimidine

A mixture of (S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidinehydrochloride (1.70 g, 5.5 mmol), 2-chloro-5-ethylpyrimidine (0.85 g,6.1 mmol) and diisopropylethylamine (1.77 g, 13.8 mmol) indimethylformamide (150 mL) was stirred at 130° C. overnight. Aftercooling to ambient temperature, dimethylformamide was removed underreduced pressure and the residue was treated with water (200 mL). Abrown precipitate was formed which was filtered and re-dissolved inmethylene chloride until the solution was clear. This was then driedover sodium sulfate, and filtered through a 3 cm silica gel pad. Thesolution was then evaporated in vacuo and the residue was purified bycolumn chromatography by eluting with hexanes-ethyl acetate mixture(4:1) to obtain the title product (1.3 g, 62%) as colorless crystals.¹H-NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.52 (d, J=8.7 Hz, 1H), 7.32(d, J=8.7 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 4.17-4.02 (m, 2H), 3.77-3.58(m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.41 (q, J=7.5 Hz, 2H),2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.12 (t, J=7.5 Hz, 3H).

Example A-85:(S)-5-Ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine

To a solution of(S)-2-(3-((4-bromo-2-fluorophenoxy)methyl]pyrrolidin-1-yl}-5-ethylpyrimidine(1.3 g, 3.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.0 g, 4.1mmol),) and potassium acetate (1.3 g, 12 mmol) in dioxane (50 mL) underargon atmosphere was added (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (170 mg, 0.2 mmol) and the mixturewas heated to 85° C. and stirred at that temperature overnight. Themixture was cooled and filtered through a pad of celite. The celite padwas washed with hot (50° C.) dioxane (100 mL) and the washings werecombined with the filtrate and evaporated to dryness. The residue wassubjected to column chromatography eluting with ether to obtain thecrude product as a light yellow oil. This oil was dissolved in hexanes(100 mL) and placed into freezer for three days. White crystals wereformed, filtered off and dried to afford the title compound (0.83 g,56%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.43 (d, J=8.7 Hz, 1H),7.34 (d, J=8.7 Hz, 1H), 7.21 (t, J=8.7 Hz, 1H), 4.19-4.05 (m, 2H),3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.41 (q, J=7.5Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.16 (s, 12H), 1.12 (t,J=7.5 Hz, 3H).

Example A-86:(S)-6-(4-((1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a solution of 3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (150 mg, 0.47 mmol) and(S)-5-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl}pyrimidine(201 mg, 0.47 mmol) in dioxane (5 mL) was added slowly a solution ofpotassium carbonate (195 mg, 1.41 mmol) in water (5 mL). After stirringunder argon for 10 minutes, (bisdiphenylphosphino) ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (24 mg, 0.03 mmol) was added and thereaction mixture was stirred at ambient temperature overnight. Water (30mL) was then added and a precipitate was formed, filtered off andair-dried. The precipitate was purified by column chromatography onsilica gel eluting with hexanes: ethyl acetate mixture (1:1) to give thetitle product (95 mg, 43%) as a white powder. ¹H-NMR (400 MHz, DMSO-d₆)δ 8.22 (s, 2H), 7.88 (d, J=8.1 Hz, 1H), 7.73 (d, J=14.0 Hz, 1H),7.64-7.54 (m, 3H), 7.33 (t, J=8.8 Hz, 1H), 5.43 (s, 2H), 4.21-4.09 (m,2H), 3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.41 (q,J=7.5 Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.12 (t, J=7.5 Hz,3H).

Example A-87:(S)-2-(3-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-5-chloropyrimidine

To a solution of (S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidinehydrochloride (4.09 g, 13.2 mmol) in dimethylformamide (15 mL) was added2,5-dichloropyrimidine (1.0 g, 14.5 mmol) and triethylamine (4.0 g, 39.6mmol). The reaction mixture was stirred and heated in “CEM” microwavesystem (150° C., 3 hours). Upon completion, the mixture was evaporatedto dryness under reduced pressure, water (50 mL) was added to theresidue and the mixture was extracted with ethyl acetate (3×50 mL). Thecombined extracts were washed with 5% aqueous solution citric acid,aqueous solution of sodium bicarbonate, brine, dried over Na₂SO₄,filtered and the filtrate was evaporated. The product was purified bycolumn chromatography on silica gel eluting with hexanes: ethyl acetate(1:1) mixture. The product was obtained as a colorless oil (4.5 g,88.2%). and used in the next step without further purification.

Example A-88:(S)-5-Chloro-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine

To a solution containing(S)-2-(3-((4-bromo-2-fluorophenoxy)methyl]pyrrolidin-1-yl}-5-chloropyrimidine(4.5 g, 11.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.0 g, 4.1mmol),) and (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (878 mg, 1.2 mmol) was added potassium acetate (1.3 g, 12mmol) in dioxane (50 mL) under argon atmosphere and the resultingmixture was stirred with heating to 90° C. overnight. The reactionmixture was then poured in mixture of ethyl acetate (100 mL) and water(100 mL). The mixture was filtered through a pad of celite and theorganic layer was separated, washed with water, brine, dried overNa₂SO₄, filtered and the filtrate was evaporated to dryness. The productwas purified by column chromatography on silica gel eluting withhexanes: ethyl acetate (1:1) mixture. The product was obtained as ayellow solid (1.9 g, 29.8%) and was used in the next step withoutfurther purification.

Example A-89:(S)-6-(4-((1-(5-Chloropyrimidin-2-yl)pyrrolidin-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a solution of(S)-5-chloro-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine(300 mg, 0.7 mmol) in dioxane (15 mL) was added3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (223mg, 0.7 mmol), 2M aqueous solution of sodium carbonate (15 mL) and(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (73mg, 0.1 mmol). The mixture was stirred and heated to 85° C. for 3 hoursand then allowed to stir at ambient temperature overnight. To themixture was then added water (50 mL) and was extracted with ethylacetate (3×30 mL). The combined extracts were washed with water, brine,dried over Na2SO4, filtered and the filtrate was evaporated to dryness.The product was purified by column chromatography on silica gel elutingwith hexanes: ethyl acetate mixture (1:1) to afford the title compound(232 mg, 69.63%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s,2H), 7.89 (d, J=8.1 Hz, 1H), 7.72 (d, J=12.7 Hz, 1H), 7.67-7.47 (m, 3H),7.32 (t, J=8.8 Hz, 1H), 5.44 (s, 2H), 4.35-4.00 (m, 2H), 3.79-3.35 (m,4H), 2.94-2.67 (m, 1H), 2.29-2.03 (m, 1H), 1.99-1.81 (m, 1H).

Example A-90:(S)-2-(3-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-4-ethylpyrimidine

To a solution of (S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidinehydrochloride (2.0 g, 6.4 mmol) in dimethylacetamide (10 mL) was added2-chloro-4-ethylpyrimidine (1.0 g, 7.0 mmol) and diisopropylethylamine(1.7 g, 12.8 mmol). The reaction mixture was stirred and heated in “CEM”microwave system (150° C., 3 hours). Upon completion, the mixture wasevaporated to dryness, and to the residue was added water and thenextracted with ethyl acetate (3×50 mL). The combined extracts werewashed with 5% aqueous citric acid, saturated aqueous solution of sodiumbicarbonate₃, brine, dried over Na₂SO₄, filtered and the filtrate wasevaporated. The crude product was purified by column chromatography onsilica gel eluting with hexanes: ethyl acetate mixture (1:1) to affordthe title product (1.8 g, 74%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 8.21 (d, J=5.0 Hz, 1H), 7.26-7.10 (m, 2H), 6.85 (t, J=8.7 Hz,1H), 6.40 (d, J=5.1 Hz, 1H), 4.04 (d, J=6.9 Hz, 2H), 3.95-3.70 (m, 2H),3.69-3.56 (m, 1H), 3.49 (dd, J=11.3, 6.6 Hz, 1H), 2.93-2.76 (m, 1H),2.62 (q, J=7.6 Hz, 2H), 2.33-2.15 (m, 1H), 2.04-1.87 (m, 1H), 1.27 (t,J=7.6 Hz, 3H).

Example A-91:(S)-4-Ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine

To a solution of:(S)-2-(3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-4-ethylpyrimidine(1.8 g, 4.7 mmol),4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.0 g, 4.1mmol), (1.42 g, 5.6 mmol) and (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (220 mg, 0.3 mmol) in 1,4-dioxane (60mL) was added potassium acetate (1.9 g, 18.8 mmol) and the resultingmixture was stirred and heated to 90° C. overnight. Upon cooling, thereaction mixture was poured into a mixture of ethyl acetate (100 mL) andwater (100 mL), then filtered through a pad of celite and the organiclayer was separated, washed with water, brine, dried over Na₂SO₄,filtered and the filtrate was evaporated to dryness. The product waspurified by column chromatography on silica gel eluting with hexanes:ethyl acetate mixture (1:1) to obtain the title product (1.9 g, 94%). asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J=5.1 Hz, 1H),7.56-7.45 (m, 2H), 6.95 (t, J=8.2 Hz, 1H), 6.38 (d, J=5.1 Hz, 1H), 4.08(d, J=6.9 Hz, 2H), 3.89 (dd, J=11.3, 7.4 Hz, 1H), 3.82-3.72 (m, 1H),3.68-3.57 (m, 1H), 3.49 (dd, J=11.4, 6.7 Hz, 1H), 2.94-2.80 (m, 1H),2.61 (q, J=7.6 Hz, 2H), 2.32-2.20 (m, 1H), 2.00-1.89 (m, 1H), 1.34 (s,12H), 1.25 (t, J=7.6 Hz, 3H).

Example A-92:(S)-6-(4-((1-(4-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3,3-dioxide

To a solution of(S)-4-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine(295 mg, 0.69 mmol) in dioxane (13 mL) was added sequentially3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (220mg, 0.69 mmol), 2M aqueous solution of sodium carbonate (1.1 mL) and(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (25mg, 0.03 mmol). The mixture was stirred and heated to 85° C. for 2hours. Upon cooling, water (50 mL) was added and the solution wasextracted with ethyl acetate (3×30 mL). The combined extracts werewashed with water, brine, dried over Na₂SO₄, filtered and the filtratewas evaporated to dryness. The product was purified by columnchromatography on silica gel eluting with hexanes: ethyl acetate mixture(1:1). The product was washed with methanol (20 mL) and air-dried toafford the title compound (85 mg, 26%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.20 (d, J=4.7 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H),7.82-7.47 (m, 4H), 7.34 (t, J=7.8 Hz, 1H), 6.49 (d, J=4.4 Hz, 1H), 5.44(s, 2H), 4.32-4.07 (m, 2H), 3.84-3.37 (m, 4H), 2.87-2.69 (m, 1H), 2.61(q, J=7.6 Hz, 2H), 2.23-2.06 (m, 1H), 1.97-1.77 (m, 1H), 1.17 (t, J=7.5Hz, 3H).

Example B-1: tert-Butyl 2,2,2-trichloroacetaimidate

To a cold solution of trichloroacetonitrile (100 g, 0.69 mol), indiethyl ether (69 mL) was added dropwise a solution of potassiumt-butoxide (69 mL, 1M in t-butanol) in diethyl ether (69 mL) maintainedat 0° C., over a period of 30 minutes. The mixture was then allowed towarm to room temperature over one hour, and was then stirred for anadditional hour with heating at reflux. The mixture was cooled to roomtemperature and evaporated under reduced pressure to yield an oil. Theoil was dissolved in hexanes (140 mL) and filtered to remove potassiumsalts. The filtrate was evaporated under reduced pressure and theresidual oil was purified by vacuum distillation. The fractiondistilling at 2.4 mm Hg and 40° C. was collected to furnish the titlecompound (105 g, 69%). ¹H-NMR (CDCl₃, 400 MHz): δ 8.21 (br, s, 1H),1.58, (s, 9H).

Example B-2: 6-tert-Butoxy-1,3-benzoxathiol-2-one

To a solution of 6-hydroxy-1,3-benzoxathiol-2-one (9.2 g, 54.7 mmol)dissolved in 100 mL of tetrahydrofuran was added at room temperature asolution of t-butyl trichloroacetaimidate (23.9 g, 109.4 mmol) intetrahydrofuran (50 mL) and boron trifluoride etherate (0.5 g, 3.5 mmol)and the mixture was stirred at room temperature overnight. Solid sodiumbicarbonate (9.24 g, 110 mmol) was then added to the solution withstirring and the solution was filtered through a silica gel column andwas washed with cold tetrahydrofuran. The filtrate was evaporated invacuo to give a yellow oil which was purified by column chromatographyeluting with methylene chloride to give6-tert-butoxy-1,3-benzoxathiol-2-one (10.4 g, 85%). ¹H-NMR (CDCl₃, 400MHz): δ 7.27 (d, J=3.8 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.92 (dd, J₁=8.6Hz, J₂=2.2 Hz, 1H), 1.39 (s, 9H).

Example B-3: 6-tert-Butoxy-1,3-benzoxathiole

To a solution of 6-tert-butoxy-1,3-benzoxathiol-2-one (10.4 g, 46.3mmol) in 200 mL of dibromomethane and 10 mL of water was addedsuccessively potassium carbonate (19.2 g, 139 mmol) and 18-crown-6-ether(1 g, 3.7 mmol). The reaction mixture was stirred and gently refluxedunder an argon atmosphere 48 hours. After cooling, the inorganic saltswere removed by filtration and the solvents were removed in vacuo. Theresidual oil was poured into methylene chloride (400 mL). The methylenechloride layer was washed with saturated sodium chloride solution (2×100mL), dried over sodium sulfate, filtered and the filtrate was evaporatedin vacuo. The residual oil was purified by column chromatography elutingwith methylene chloride to furnish 6-tert-butoxy-1,3-benzoxathiole (8.8g, 90%). ¹H-NMR (CDCl₃, 400 MHz): δ 7.04 (d, J=8.1 Hz, 1H), 6.55 (m,2H), 5.71 (s, 2H), 1.33 (s, 9H).

Example B-4: 1,3-Benzoxathiol-6-ol

Trifluoroacetic acid (20 mL) was added to a solution of6-tert-butoxy-1,3-benzoxathiole (1.5 g, 7.1 mmol) in methylene chloride(50 mL) and the mixture was cooled to 0° C. The mixture was stirred for1 hour at 0° C. and then allowed to warm to room temperature. Thesolvents were removed under reduced pressure and the residue wasdissolved in CH₂Cl₂ (30 mL) and purified by column chromatographyeluting with CH₂Cl₂:CH₂Cl₂:Et₂O (1:1) to give 1,3-benzoxathiol-6-ol(0.45 g, 41%). ¹H-NMR (CDCl₃, 400 MHz): δ 6.99 (d, J=8.1 Hz, 1H),6.44-6.38 (m, 2H), 5.70 (s, 2H), 4.90 (br s, 1H).

Example B-5: 1,3-Benzoxathiol-6-trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (0.82 g, 2.9 mmol) was added dropwiseto a solution of 1,3-benzoxathiol-6-ol (0.45 g, 2.9 mmol) in 10 mL ofpyridine at 0° C. The mixture was stirred for 30 minutes at 0° C. andthen allowed to warm to room temperature with stirring overnight. Thereaction mixture was then evaporated to dryness and the residual oil wasdissolved in 50 mL of methylene chloride and washed with 50 mL of 10%aqueous solution of citric acid, 50 mL of saturated sodium chloridesolution and then with 100 mL of water. The organic layer separated anddried over sodium sulfate, filtered and the filtrate was evaporated invacuo. The residue was dissolved in methylene chloride (20 mL) and waspurified by column chromatography eluting with methylene chloride togive 1,3-benzoxathiol-6-yl trifluoromethanesulfonate (8) (0.81 g, 97%).¹H-NMR (CDCl₃, 400 MHz): δ 7.18 (d, J=8.4 Hz, 1H), 6.82 (dd, J₁=2.3 Hz,J₂=8.4 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 5.81 (s, 2H).

Example B-6:tert-butyl-4-((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(100.0 g, 0.46 mol) and triethylamine (94.0 g, 0.93 mol) indichloromethane (1500 mL) at 0° C. was added methanesulfonyl chloride(58.5 g, 0.51 mol). The reaction mixture was stirred at ambienttemperature for 4 hours and then washed sequentially with 0.1Nhydrochloric acid (500 mL) and brine (300 mL). The organic layer wasseparated, dried over sodium sulfate, filtered and the filtrate wasconcentrated in vacuo to afford the title compound (120.1 g, 88%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 4.06 (d, J=6.3 Hz, 2H), 3.95(m, 2H), 3.16 (s, 3H), 2.71 (br s, 2H), 1.86 (m, 1H), 1.64 (d, J=12.7Hz, 2H), 1.39 (s, 9H), 1.09 (m, 2H).

Example B-7:Tert-Butyl-4-((4-bromo-2-fluorophenoxy)methyl)piperidine-1-carboxylate

A suspension containingtert-butyl-4-((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (80.0g, 0.27 mol), 4-bromo-2-fluorophenol (62.5 g, 0.33 mol) and potassiumcarbonate (75.4 g, 0.55 mol) in dimethylsulfoxide (800 mL) was stirredat 110° C. for 16 hours. Upon completion of reaction as evidenced bythin layer chromatography, dimethylsulfoxide was distilled off underreduced pressure. The residual oil was quenched with water (800 mL) andthe resultant precipitate was filtered off and re-crystallized fromisopropanol to afford tert-butyl-4-((4-bromo-2-fluoro phenoxy)methyl)pyperidine-1-carboxylate (88.0 g, 83.1%) as a white crystalline powder:¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (dd, J=10.8, 2.3 Hz, 1H), 7.30 (m, 1H),7.15 (m, 1H), 3.96 (d, J=10.7 Hz, 2H), 3.90 (d, J=6.4 Hz, 2H), 2.66-2.79(m, 2H), 1.89-1.98 (m, 1H), 1.72 (d, J=10.9 Hz, 2H), 1.39 (s, 9H),1.09-1.23 (m, 2H).

Example B-8:tert-Butyl-4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy]methyl)piperidine-1-carboxylate

To a mixture oftert-butyl-4-((4-bromo-2-fluorophenoxy)methyl)piperidine-1-carboxylate(60.0 g, 0.15 mol) and4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane (51.0 g, 0.2mol) in acetonitrile (1000 mL) was added of 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) (Pd(dppf)Cl₂(5.63 g, 8 mmol) and potassium acetate (45.5 g, 0.46 mol) and thesolution was stirred under argon at 70° C. for 16 hours. Uponcompletion, the reaction mixture was diluted with ethyl acetate (1000mL) and washed with brine (1000 mL). The organic layers were combined,dried over magnesium sulfate, filtered and the filtrate was evaporatedunder reduced pressure. The residue after evaporation was purified bycolumn chromatography eluting with hexanes-ethyl acetate mixture (10 1)to afford the title compound (50.0 g, 74.3%) as a white powder. ¹H NMR(400 MHz, DMSO-d₆) δ 7.42 (d, J=8.1 Hz, 1H), 7.31 (m, 1H), 7.15 (m, 1H),3.91-4.02 (m, 4H), 2.66-2.80 (m, 2H), 1.89-2.02 (m, 1H), 1.73 (d, J=11.2Hz, 2H), 1.39 (s, 9H), 1.27 (s, 12H), 1.07-1.22 (m, 2H).

Example B-9:(1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)methylmethanesulfonate

Step 1: A suspension of piperidin-4-ylmethanol (124.6 g, 1.08 mol) and2,5-dichloropyrimidine (161.2 g, 1.08 mol) and triethylamine (438 g, 4.3mol) in acetonitrile (1000 mL) was heated under reflux for 16 hours.Upon cooling to room temperature, a precipitate was formed which wasfiltered, washed with ether (300 mL) and dried to afford(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)methanol (203.2 g, 82.4%) as abeige powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 2H), 4.58 (d, J=13.3Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 3.26 (t, J=5.7 Hz, 2H), 2.87 (td,J=12.7, 2.2 Hz, 2H), 1.67 (m, 3H), 1.05 (m, 2H).

Step 2: To a solution of(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate (203g, 0.89 mol) and triethylamine (180.4 g, 1.78 mol) in dichloromethane(1500 mL) at 0° C. was added methanesulfonyl chloride (112.34 g, 0.98mol). The reaction mixture was stirred at ambient temperature for 4hours and then washed sequentially with 0.1N hydrochloric acid solution(500 mL) and brine (300 mL). The organic layer was separated, dried oversodium sulfate, filtered and the filtrate was concentrated in vacuo toafford the title compound (120.1 g, 88%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.22 (s, 2H), 4.76 (d, J=13.5 Hz, 2H), 4.10 (d, J=6.6 Hz,2H), 3.02 (s, 3H), 2.90 (td, J=12.9, 2.5 Hz, 2H), 2.06 (m, 1H), 1.84 (d,J=12.5, 2H), 1.30 (m, 2H).

Example B-10:2-(4-((4-Bromo-2-fluorophenoxy)methyl]piperidin-1-yl}-5-chloropyrimidine

A suspension of (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)methylmethanesulfonate (244.3 g, 0.8 mol), 4-bromo-2-fluorophenol (206.0 g,1.07 mol) and potassium carbonate (331.0 g, 2.4 mol) indimethylsulfoxide (2.5 L) was stirred at 110° C. for 16 hours. Uponcompletion dimethylsulfoxide was distilled off under reduced pressureand a residue was treated with water (2.0 L). A solid precipitate wasfiltered off and re-crystallized from isopropanol (1.5 L) to afford thetitle product (246.1 g, 77%) as a white crystalline powder: ¹H NMR (400MHz, CDCl₃) δ 8.22 (s, 2H), 7.24 (dd, J=10.5, 2.3 Hz, 1H), 7.18 (dt,J=8.7, 1.9 Hz, 1H), 6.83 (t, J=8.8 Hz, 1H), 4.77 (d, J=13.4 Hz, 2H),3.87 (d, J=6.5 Hz, 2H),), 2.94 (td, J=12.9, 2.5 Hz, 2H), 2.14 (m, 1H),1.93 (d, J=12.4 Hz, 2H), 1.34 (qd, J=12.5, 4.2 Hz, 2H).

Example B-11:9-Chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine

A mixture of2-(4-((4-bromo-2-fluorophenoxy)methyl)piperidin-1-yl)-5-chloropyrimidine(246.0 g, 0.6 mol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane (187.0 g,0.746 mol), Pd(dppf)Cl₂ (22.5 g, 0.05 mol) and potassium acetate (241.0g, 2.45 mol) in acetonitrile (2.5 L) was stirred under argon at 70° C.for 16 hours. Upon completion the reaction mixture was diluted withethyl acetate (2.0 L) and washed with brine (1.0 L). The organic phasewas separated, dried over magnesium sulfate, filtered and the filtratewas evaporated under reduced pressure. The residue after evaporation wassubjected to column chromatography eluting with hexanes-ethyl acetatemixture 10:1 by volume to afford the title product (234.8 g, 85.4%) as awhite powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 7.42 (d, J=8.2Hz, 1H), 7.31 (d, J=11.7, 1.85 Hz, 1H), 1.27 (s, 12H), 7.15 (t, J=8.2Hz, 1H), 4.61 (d, J=13.5 Hz, 2H), 3.96 (d, J=6.5 Hz, 2H), 2.94 (t, J=14Hz, 2H), 2.06 (m, 1H), 1.82 (d, J=13.5 Hz, 2H).

Example B-12:2-(4-((4-Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy]methyl)piperidin-1-yl)-5-chloropyrimidine

To a solution of5-chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine(0.5 g, 1.1 mmol) in dioxane (30 mL) was added 1,3-benzoxathiol-6-yltrifluoromethanesulfonate (0.32 g, 1.1 mmol) and cesium carbonate (1 g,3 mmol). The reaction mixture was purged with argon and 1,1′(bisdiphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl₂(0.1 g, 0.1 mmol) was added and the resultant solution was stirred atroom temperature for 1 hour and then heated at 60° C. for 12 hours.After cooling, the solvents were evaporated in vacuo and the residualoil was purified by column chromatography eluting withCH₂Cl₂:CH₂Cl₂:Et₂O (1:1) to give the title compound (0.08 g, 16%).¹H-NMR (400 MHz, DMSO-d₆): δ 8.40 (s, 2H), 7.52 (d, J=12.1 Hz, 1H), 7.40(d, J=7.3 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.18 (m, 3H), 5.80 (s, 2H),4.64 (d, J=12.0 Hz, 2H), 3.97 (d, J=5.1 Hz, 2H), 2.96 (t, J=12.2 Hz,2H), 2.11 (m, 1H), 1.85 (d, J=11.4 Hz, 2H), 1.25 (m, 2H).

Example B-13: 6-tert-Butoxy-1,3-benzoxathiole 3-oxide

m-Chloroperbenzoic acid (70%, 5.25 g, 21.3 mmol) was added to a solutionof 6-tert-butoxy-1,3-benzoxathiole (4.48 g, 21.3 mmol)) dissolved in 100mL of CH₂Cl₂ and cooled to 0° C. The reaction mass was stirred 2 hoursat 0° C. and filtered to remove a precipitate. The filtrate was washedwith sodium carbonate solution (2×100 mL), dried over sodium sulfate andfiltered. The solvent was evaporated in vacuo and the residual oil waspurified by column chromatography eluting with CH₂Cl₂:CH₂Cl₂:Et₂O (1:1)to furnish 6-tert-butoxy-1,3-benzoxathiole 3-oxide (4 g, 83%). ¹H-NMR(400 MHz, CDCl₃): δ 7.74 (d, J=8.2 Hz, 1H), 6.79 (m, 2H), 5.48 (d,J=11.0 Hz, 1H), 5.04 (d, J=11.0 Hz, 1H), 1.44 (s, 9H).

Example B-14: 1,3-Benzoxathiol-6-ol 3-oxide

To a solution of 6-tert-butoxy-1,3-benzoxathiole 3-oxide (4 g, 17.6mmol) dissolved in methylene chloride (50 mL) was added trifluoroaceticacid (20 mL) and the resultant solution was stirred for 1 hour at roomtemperature followed by evaporation of solvents in vacuo. The residualoil was poured into ether and the precipitate formed was filtered offand dried to yield 1,3-benzoxathiol-6-ol 3-oxide (1.9 g, 63%). ¹H-NMR(400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 6.62 (m,2H), 5.52 (d, J=11.0 Hz, 1H), 5.15 (d, J=1.0 1 Hz, 1H).

Example B-15: 3-Oxido-1,3-benzoxathiol-6-yl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (3.15 g, 1.1 mmol) was added dropwiseto a solution of 1.9 g (11.1 mmole) of 1,3-benzoxathiol-6-ol 3-oxide(1.9 g, 11.1 mmol) in 20 mL of pyridine at 0° C. The mixture was stirredfor 30 minutes at that temperature and overnight at room temperature.The reaction mixture was then evaporated to dryness and the residual oilwas dissolved in 100 mL of methylene chloride and washed consecutivelywith 100 mL of 10% aqueous solution of citric acid, 100 mL of saturatedsodium chloride solution and then with 100 mL of water. The organiclayer was dried over sodium sulfate, filtered and the filtrate wasevaporated in vacuo. The residual oil was dissolved in methylenechloride (20 mL) and was purified by column chromatography eluting withCH₂Cl₂ to give 3-oxido-1,3-benzoxathiol-6-yl trifluoromethanesulfonate(1.79 g, 53%). ¹H-NMR (400 MHz, CDCl₃): δ 7.99 (d, J=8.6 Hz, 1H), 7.18(d, J=2.1 Hz, 1H), 7.13 (dd, J₁=2.1 Hz, J₂=8.6 Hz, 1H), 5.61 (d, J=11.1Hz, 1H), 5.14 (d, J=11.1 Hz, 1H).

Example B-16:6-(4-((1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of5-chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine(0.63 g, 1.4 mmol) in dioxane (30 mL) was added3-oxido-1,3-benzoxathiol-6-yl trifluoromethanesulfonate (0.43 g, 1.4mmol) and cesium carbonate (1 g, 3 mmol) and stirred at roomtemperature. The reaction mixture was purged with argon and 1,1′(bisdiphenylphosphino)ferrocenepalladium(II) dichloride (Pd(dppf)Cl₂(0.1 g, 0.1 mmol) was added and the resultant solution was stirred atroom temperature for 1 hour and then heated at 60° C. for 2 hours. Aftercooling, the solvents were evaporated in vacuo and the residual oil waspurified by column chromatography eluting with CH₂Cl₂:Et₂O (1:1) tofurnish the title compound (0.35 g, 52%). ¹H-NMR (400 MHz, CDCl₃): δ8.23 (s, 2H), 7.92 (d, J=8.4 Hz, 1H), 7.38-7.30 (m, 4H), 7.04 (t, J=8.3Hz, 1H), 5.55 (d, J=11.0 Hz, 1H), 5.06 (d, J=11.0 Hz, 1H), 4.78 (d,J=13.0 Hz, 2H), 3.96 (d, J=6.0 Hz, 2H), 2.96 (t, J=12.5 Hz, 2H), 2.20(m, 1H), 1.99 (d, J=12.3 Hz, 2H), 1.38 (m, 2H).

Example B-17: tert-Butyl4-((2-fluoro-4-(3-oxido-1,3-benzoxathiol-6-yl)phenoxy)methyl)piperidine-1-carboxylate

A solution oftert-butyl-4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy]methyl)piperidine-1-carboxylate(0.6 g, 1.4 mmol), 3-oxido-1,3-benzoxathiol-6-yltrifluoromethanesulfonate (0.43 g, 1.4 mmol) and cesium carbonate (1 g,3 mmol) in dioxane (30 mL) was purged with argon and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) (Pd(dppf)Cl₂ (0.1g, 0.1 mmol). The resulting solution was stirred at ambient temperaturefor 1 hour and then heated at 60° C. for 2 hours. After cooling, thevolatiles were evaporated in vacuo and the residual oil was subjected tocolumn chromatography on silica gel, eluting with dichloromethane-ethermixture 1:1 to afford the title compound (0.51 g, 80%) as a white solid.¹H-NMR (400 MHz, CDCl₃): δ 7.92 (d, J=8.4 Hz, 1H), 7.38-7.29 (m, 4H),7.04 (t, J=8.6 Hz, 1H), 5.54 (d, J=11.1 Hz, 1H), 5.06 (d, J=11.1 Hz,1H), 4.19 (bs, 2H), 3.94 (d, J=6.5 Hz, 2H), 2.78 (t, J=12.8 Hz, 2H),2.10-2.00 (m, 1H), 1.87 (d, J=12.8 Hz, 2H), 1.48 (s, 9H), 1.36-1.25 (m,2H).

Example B-18:6-(3-Fluoro-4-(piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of tert-butyl4-((2-fluoro-4-(3-oxido-1,3-benzoxathiol-6-yl)phenoxy)methyl)piperidine-1-carboxylate (0.51 g, 1.1 mmol) in methylene chloride (10mL) was added trifluoroacetic acid (5 mL) and the resulting mixture wasstirred at 40° C. for 4 hours. Upon completion the volatiles weredistilled off in vacuo and a residue after evaporation was withsonicated with ether. A formed precipitate was filtered off to affordupon drying the title compound (0.47 g, 90%) as a white solid. Thematerial was used in the next step without further purification.

Example B-19:6-(4-((1-(5-Ethylpyrimidin-2-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole-3-oxide

A solution of6-(3-fluoro-4-(piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide. (0.27 g, 0.57 mmol)), 2-chloro-5-ethylpyrimidine (0.086 g, 0.6mmol) and triethylamine (0.23 g, 2.3 mmol) in acetonitrile (50 mL) wasstirred at reflux for 6 hours. Upon completion, the reaction mixture wasallowed to come to ambient temperature and a formed precipitate wasfiltered off and filter cake was washed consequently with water and withhexane to allow a crude product. The crude product was subjected tocolumn chromatography eluting with dichloromethane to obtain the titleproduct (0.2 g, 75%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 2H), 8.08 (d,J=7.9 Hz, 1H), 7.69 (d, J=12.8 Hz, 1H), 7.62 (s, 1H), 7.59-7.49 (m, 2H),7.28 (t, J=8.9 Hz, 1H), 5.64 (d, J=11.0 Hz, 1H), 5.22 (d, J=11.0 Hz,1H), 4.67 (d, J=12.7 Hz 2H), 4.01 (d, J=6.1 Hz, 2H), 2.89 (t, J=12.5 Hz,2H), 2.46-2.39 (m, 2H), 2.15-2.05 (bs, 1H), 1.84 (d, J=11.9 Hz, 2H),1.31-1.19 (m, 2H), 1.13 (t, J=7.3 Hz, 3H).

Example B-20: 2-Oxobenzo[d][1,3]oxathiol-5-yl-trifluoromethanesulfonate

To a solution of 5-hydroxy-1,3-benzoxathiol-2-one (5.1 g, 30.0 mmol)dissolved in 50 mL of pyridine was added trifluoromethanesulfonicanhydride (10.3 g, 36.0 mmol) at 0° C. and the reaction mixture wasstirred for 40 minutes at that temperature and then stirred at roomtemperature overnight. The solvent was evaporated in vacuo and theresidue was treated with ethyl acetate (70 mL) to give a suspensionwhich was washed with 10% citric acid (70 mL) followed by brine (50 mL)and water (50 mL). The organic layer collected, dried over magnesiumsulfate, filtered and evaporated in vacuo to give an oil which waswashed with ether (50 mL) and purified by column chromatography elutingwith methylene chloride to give 5-tert-butoxy-1,3-benzoxathiol-2-one(10.4 g, 85%). H-NMR (400 MHz, CDCl₃): δ, 7.41 (d, J=2.6 Hz, 1H), 7.39(d, J=8.9 Hz, 1H), 7.28 (m, 1H).

Example B-21: Benzo[d][1,3]oxathiol-5-yl-trifluoromethanesulfonate

To a solution of2-oxobenzo[d][1,3]oxathiol-5-yl-trifluoromethanesulfonate (1.4 g, 4.7mmol) in 25 mL of dibromomethane and 2 mL of water was addedsuccessively potassium carbonate (2.6 g, 20 mmol) and 18-crown-6-ether(0.2 g, 0.8 mmol). The reaction mixture was stirred and gently refluxedunder an argon atmosphere 48 hours. After cooling, the inorganic saltswere removed by filtration and the solvents were removed in vacuo. Theresidual oil was poured into methylene chloride (150 mL). The methylenechloride layer was washed with saturated sodium chloride solution (2×100mL), dried over sodium sulfate, filtered and the filtrate was evaporatedin vacuo. The residual oil was treated with ether (50 mL) and cooled ina dry ice bath for 30 minutes. A precipitate was formed which wasfiltered, washed with ether (20 mL) and collected to furnish the titlecompound (0.8 g, 60%). ¹⁹F NMR (377 MHz, benzene-d₆) δ 72.64 (s, 1F).

Example B-22:3-Oxido-benzo[d][1,3]oxathiol-5-yl-trifluoromethanesulfonate

m-Chloroperbenzoic acid (70%, 0.48 g, 2.8 mmol) was added to a solutionof benzo[d][1,3]oxathiol-5-yl trifluoromethanesulfonate (0.8 g, 2.8mmol)) in dichloromethane (30 mL) at 0° C. The reaction mixture wasstirred for 2 hours at that temperature and then was filtered to removea precipitate. The filtrate was washed with saturated solution sodiumcarbonate (2×20 mL), dried over sodium sulfate and filtered. Thefiltrate was evaporated in vacuo and the residual oil was purified bycolumn chromatography on silica gel eluting with dichloromethane-ethermixture (1:1) to afford the title product (0.6 g, 70%). ¹⁹F NMR (377MHz, benzene-d₆) δ 72.49 (s, 1F).

Example B-23:1-(4-((2-Fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)phenoxy)methyl)-piperidin-1-yl)-3-methylbutane-1-one

To a suspension of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole-3-oxidehydrochloride (0.5 g, 1.4 mmol) and 3-methylbutanoic acid (0.15 g, 1.5mmol) in acetonitrile (15 mL) was added triethylamine (0.43 g, 4.2 mmol)andN-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminiumhexafluorophosphate (0.68 g, 1.8 mmol). The resulting solution wasstirred at 40° C. for 24 hours. Upon cooling, a precipitate was formedwhich was filtered off and dried to afford the title compound (0.4 g,64%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (d, J=8.2 Hz, 1H), 7.69 (dd,J=12.8, 2.1 Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.57 (d, J=9.5 Hz, 1H),7.51 (dd, J=8.1, 1.3 Hz, 1H), 7.28 (t, J=8.9 Hz, 1H), 5.64 (d, J=11.4Hz, 1H), 5.23 (d, J=11.4 Hz, 1H), 4.43 (d, J=13.7 Hz, 1H), 3.99 (d,J=6.1 Hz, 2H), 3.92 (d, J=14.1 Hz, 1H), 3.03 (t, J=13.6 Hz, 1H), 2.52(m, 2H), 2.19 (d, J=7.0 Hz, 2H), 1.91-2.11 (m, 2H), 1.80 (t, J=16.7 Hz,2H), 1.06-1.27 (m, 2H), 0.90 (d, J=6.6 Hz, 6H).

Example B-24:6-(3-Fluoro-4-((1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole 3-oxide

A suspension of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole-3-oxidehydrochloride (0.20 g, 0.65 mmol), 2-chloro-5-methoxypyrimidine (0.13 g,0.90 mmol) and cesium carbonate (0.25 g, 0.75 mmol) in dimethylacetamide(10 mL) was heated in CEM microwave system at 130° C. for 3 hours. Thereaction mixture was cooled to ambient temperature and extracted with amixture of ethyl acetate (100 mL) and water (100 mL). The layers wereseparated and the aqueous phase was extracted with ethyl acetate (2×30mL). The combined organic layers were dried over sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theoily residue was washed with methanol (20 mL) to form a solid materialwas filtered off and air-dried. This material was subjected to columnchromatography on silica gel eluting with ethyl acetate-hexanes mixture(1:1) to afford the title compound as a white solid (76 mg, 27%). ¹H NMR(400 MHz, DMSO-d₆) δ 8.19 (s, 2H), 8.07 (d, J=7.8 Hz, 1H), 7.69 (m, 1H),7.63 (s, 1H), 7.49-7.59 (m, 2H), 7.28 (t, J=8.6 Hz, 1H), 5.63 (d, J=11.4Hz, 1H), 5.24 (d, J=11.4 Hz, 1H), 4.56 (d, J=13.2 Hz, 2H), 4.01 (d,J=6.4 Hz, 2H), 3.76 (s, 3H), 2.88 (t, J=11.6 Hz, 2H), 2.08 (m, 1H), 1.82(d, J=13.3 Hz, 2H), 1.18-1.32 (m, 2H).

Example B-25:6-(4-((1-(4-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-3-(fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a suspension of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole-3-oxidehydrochloride (0.25 g, 0.70 mmol), and 2-chloro-4-ethylpyrimidine (0.12g, 0.83 mmol) in acetonitrile (10 mL) was added triethylamine (0.13 g,1.04 mmol) and the mixture was heated under reflux overnight. Thesolvent was then removed under reduced pressure and the residue wastriturated with water (20 mL). A solid precipitate was filtered off,washed with methanol (10 mL) and air-dried to afford the title compound(0.21 g, 65%) as a light yellow powder. ¹H-NMR (400 MHz, DMSO-d₆): δ8.21 (d, J=4.9 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.70 (d, J=12.7 Hz, 1H),7.63 (s, 1H), 7.60-7.48 (m, 2H), 7.28 (t, J=8.8 Hz, 1H), 6.48 (d, J=4.9Hz, 1H), 5.64 (d, J=11.5 Hz, 1H), 5.22 (d, J=11.5 Hz, 1H), 4.75 (d,J=12.8 Hz, 2H), 4.01 (d, J=6.5 Hz, 2H), 2.89 (t, J=12.8 Hz, 2H), 2.54(q, J=7.6 Hz, 2H), 2.18-2.02 (m, 1H), 1.85 (d, J=12.8 Hz, 2H), 1.31-1.17(m, 5H).

Example B-26:2-(4-((4-Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-4-ethylpyrimidine

To a solution of6-(4-((1-(4-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-3-(fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide (90 mg, 0.19 mmol) in tetrahydrofuran (10 mL) under argon wasadded a solution of borane dimethylsulfide complex solution intetrahydrofuran (2M, 0.3 mL, 0.57 mmol) and the mixture was stirred atreflux for 3 hours. After the reaction was complete, the solution wascooled to room temperature and the solution was carefully quenched withmethanol (1-2 mL) dropwise, and the resulting mixture was stirred atambient temperature for 2 hours. The solvents were then removed in vacuoand the residue was subjected to column chromatography on silica geleluting with chloroform-methanol mixture (40:1) to afford the titlecompound (58 mg, 67%) of as a white powder. ¹H-NMR (DMSO-d₆, 400 MHz): δ8.21 (d, J=4.9 Hz, 1H), 7.52 (d, J=12.7 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H),7.33 (d, J=7.7 Hz, 1H), 7.25-7.16 (m, 2H), 6.48 (d, J=4.9 Hz, 1H), 5.80(s, 1H), 4.74 (d, J=12.8 Hz, 2H), 3.97 (d, J=6.5 Hz, 2H), 2.88 (t,J=12.8 Hz, 2H), 2.54 (q, J=7.6 Hz, 2H), 2.15-2.01 (m, 1H), 1.84 (d,J=12.8 Hz, 2H), 1.31-1.12 (m, 5H).

Example B-27:6-(4-((1-(5-Ethoxypyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A suspension of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole3-oxide hydrochloride (0.21 g, 0.60 mmol), 2-chloro-5-ethoxypyrimidine(0.14 g, 0.90 mmol) and cesium carbonate (0.25 g, 0.75 mmol) indimethylacetamide (10 mL) was heated in CEM microwave system at 130° C.for 3 hours. The reaction mixture was cooled to ambient temperature andextracted with a mixture of ethyl acetate (100 mL) and water (100 mL).The layers were separated and the aqueous phase was extracted with ethylacetate (2×30 mL). The combined organic layers were dried over sodiumsulfate, filtered, and the filtrate was concentrated under reducedpressure. The oily residue was washed with methanol (20 mL) to form asolid material was filtered off and air-dried. This material wassubjected to column chromatography on silica gel eluting with ethylacetate-hexanes mixture (1:1) to afford the title compound as a whitesolid (71 mg, 25%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 2H), 8.07 (d,J=8.0 Hz, 1H), 7.73-7.48 (m, 4H), 7.28 (t, J=9.0 Hz, 1H), 5.64 (d,J=11.5 Hz, 1H), 5.22 (d, J=11.5 Hz, 1H), 4.58 (d, J=13.7 Hz, 2H),4.07-3.96 (m, 4H), 2.87 (t, J=11.6 Hz, 2H), 2.14-2.02 (m, 1H), 1.82 (d,J=13.3 Hz, 2H), 1.34-1.19 (m, 5H).

Example B-28:6-(3-Fluoro-4-((1-(5-isopropylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A suspension of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole3-oxide hydrochloride (0.20 g, 0.55 mmol),2-chloro-5-isopropylpyrimidine (0.09 g, 0.57 mmol) and triethylamine(0.23 g, 2.3 mmol) in dimethylformamide (10 mL) was heated at 50° C. for3 hours. The reaction mixture was cooled to ambient temperature anddiluted with water (10 mL) to form a precipitate which was filtered offand washed with cold water and hexanes. This material was subjected tocolumn chromatography on silica gel eluting with dichloromethane toafford the title compound as a white solid 0.21 g, 81%). ¹H NMR (400MHz, DMSO-d₆) δ 8.27 (s, 2H), 8.07 (d, J=8.2 Hz, 1H), 7.70 (d, J=12.2Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H),7.27 (t, J=8.6 Hz, 1H), 5.64 (d, J=11.9 Hz, 1H), 5.22 (d, J=11.9 Hz,1H), 4.67 (d, J=12.8 Hz, 2H), 4.02 (d, J=5.7 Hz, 2H), 2.89 (t, J=12.5Hz, 2H), 2.80-2.72 (m, 1H), 2.15-2.05 (bs, 1H), 1.84 (d, J=12.3 Hz, 2H),1.31-1.20 (m, 2H), 1.18 (d, J=6.8 Hz, 6H).

Example B-29:6-(3-Fluoro-4-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole 3-oxide

A suspension of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole-3-oxidehydrochloride (0.20 g, 0.55 mmol), 2-chloro-5-(trifluoromethyl)pyridine(0.11 g, 0.60 mmol) and triethylamine (0.20 g, 2.0 mmol) indimethylformamide (10 mL) was heated at 50° C. for 3 hours. The reactionmixture was cooled to ambient temperature and diluted with water (10 mL)to form a precipitate which was filtered off and washed with cold waterand hexanes. This material was subjected to column chromatography onsilica gel eluting with dichloromethane to afford the title compound asa white solid 0.20 g, 71%). %). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s,1H), 7.92 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.40-7.30 (m, 4H),7.05 (t, J=8.6 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H), 5.55 (d, J=11.1 Hz, 1H),5.07 (d, J=11.1 Hz, 1H), 4.51 (d, J=13.3 Hz, 2H), 3.97 (d, J=6.5 Hz,2H), 3.01 (t, J=12.8 Hz, 2H), 2.27-2.17 (bs, 1H), 2.02 (d, J=12.7 Hz,2H), 1.49-1.37 (m, 2H).

Example B-30: Resolution of 6-hydroxy-2H-benzo[d][1,3]oxathiole 3-oxide;(S)-6-hydroxy-2H-benzo[d][1,3]oxathiole 3-oxide and(R)-6-hydroxy-2H-benzo[d][1,3]oxathiole 3-oxide

Preparative chiral resolution was carried out employing the followingconditions: Shimadzu system SIL-10Ap; pump LC-20Ap x2; SPD-M20A UVdetector; CBM-20A control unit; FRC-10A fraction collector; LC solutionsoftware; Preparative column: Phenomenex Lux 5u Cellulose-4 AXIA F250×30.00; eluent: isocratic 20 mL/min hexane\isopropyl alcohol(IPA)\formic acid (HCOOH) 850/150/4 temperature 23° C.; column load 50mg of sample (in 8 mL IPA+200 uL (HCOOH); detector set: UV 262 nm. 2 gload of 6-hydroxy-2H-benzo[d][1,3]oxathiole 3-oxide First fraction wascollected from 49-56 minutes 930 mg (yield 93%; ee 99.8%) Secondfraction was collected from 58-69 minutes 850 mg (yield 85%; ee 97.2%)Analytical control was carried out at analytical chromatography complex:Pump: Shimadzu LC-20; Control unit: CBM-10; autosampler: SIL-10AD;thermostat: LCT 5100; detector: Jasco model CD-2095 circular dichroismchiral detector/UV detector; column: Phenomenex Cellulose-4 4.5×50 mm 3uM; precolumn: Phenomenex Cellulose-4 4.5×3 mm 3 uM; Software: LCSolution; eluent: isocratic 1 ml\min Hexane\IPA\HCOOH 850\150\4 23° C.with detection on UV and CD at 262 nm First enantiomer: retentiontime=4.92 minutes (CD negative) Second enantiomer: retention time=5.85minutes (CD positive)

Example B-31: (S)-3-Oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate

The enantiomer with a retention time of 4.92 minutes (0.25 g, 1.4 mmol)was dissolved in pyridine (20 mL) and a solution oftrifluoromethanesulfonic anhydride (0.45 g, 1.6 mmol) at 0° C. was addedand the mixture was stirred for 30 minutes at that temperature and thenat ambient temperature overnight. Upon completion the volatiles wereevaporated and a residue after evaporation was dissolved indichloromethane (10 mL). The organic solution was consequently washedwith 10% aqueous solution citric acid (10 mL), saturated sodium chloridesolution (10 mL) and water (10 mL). The organic layer was dried oversodium sulfate, filtered and the filtrate was evaporated in vacuo. Theresidue was subjected to column chromatography on silica gel elutingwith dichloromethane to afford the title compound (0.12 g, 27%) as awhite solid. %). ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=8.6 Hz, 1H),7.18 (d, J=2.1 Hz, 1H), 7.13 (dd, J₁=2.1 Hz, J₂=8.6 Hz, 1H), 5.61 (d,J=11.1 Hz, 1H), 5.14 (d, J=11.1 Hz, 1H

Example B-32:(S)-6-(4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A solution of5-chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine(0.18 g, 0.4 mmol) in dioxane (30 mL) was treated with(S)-6-((trifluoromethyl)sulfonyl)-2H-benzo[d][1,3]oxathiole 3-oxide(0.12 g, 0.4 mmol) and cesium carbonate (0.3 g, 1 mmol) under argon. Thereaction mixture was purged with argon and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (0.03g, 0.03 mmol) was slowly added followed by stirring at ambienttemperature for 1 hour and then at 60° C. for an additional 2 hours.Upon completion, the volatiles were evaporated in vacuo and the residuewas subjected to column chromatography on silica gel eluting withdichloromethane-ether mixture (1:1) to afford the title compound (6 mg,3%). (400 MHz, DMSO-d₆) δ 8.23 (s, 2H), 7.92 (d, J=8.4 Hz, 1H),7.38-7.30 (m, 4H), 7.04 (t, J=8.3 Hz, 1H), 5.55 (d, J=11.0 Hz, 1H), 5.06(d, J=11.0 Hz, 1H), 4.78 (d, J=13.0 Hz, 2H), 3.96 (d, J=6.0 Hz, 2H),2.96 (t, J=12.5 Hz, 2H), 2.20 (m, 1H), 1.99 (d, J=12.3 Hz, 2H), 1.38 (m,2H).

Example B-33: (R)-3-Oxido-2H-benzo[d][1,3]oxathiol-6-ylTrifluoromethanesulfonate

The enantiomer with a retention time of 5.85 minutes (0.25 g, 1.4 mmol)was dissolved in pyridine (20 mL) and a solution oftrifluoromethanesulfonic anhydride (0.45 g, 1.6 mmol) at 0° C. was addedand the mixture was stirred for 30 minutes at that temperature and thenat ambient temperature overnight. Upon completion the volatiles wereevaporated and a residue after evaporation was dissolved indichloromethane (10 mL). The organic solution was consequently washedwith 10% aqueous solution citric acid (10 mL), saturated sodium chloridesolution (10 mL) and water (10 mL). The organic layer was dried oversodium sulfate, filtered and the filtrate was evaporated in vacuo. Theresidue was subjected to column chromatography on silica gel elutingwith dichloromethane to afford the title compound (0.23 g, 54%) as awhite solid. %). ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=8.6 Hz, 1H),7.18 (d, J=2.1 Hz, 1H), 7.13 (dd, J₁=2.1 Hz, J₂=8.6 Hz, 1H), 5.61 (d,J=11.1 Hz, 1H), 5.14 (d, J=11.1 Hz, 1H).

Example B-34:(R)-6-(4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole-3-oxide

A solution of5-chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine(0.34 g, 0.76 mmol) in dioxane (30 mL) was treated with(R)-6-((trifluoromethyl)sulfonyl)-2H-benzo[d][1,3]oxathiole 3-oxide(0.23 g, 0.76 mmol) and cesium carbonate (0.6 g, 2 mmol) under argon.The reaction mixture was purged with argon and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (0.06g, 0.06 mmol) was slowly added followed by stirring at ambienttemperature for 1 hour and then at 60° C. for an additional 2 hours.Upon completion, the volatiles were evaporated in vacuo and the residuewas subjected to column chromatography on silica gel eluting withdichloromethane-ether mixture (1:1) to afford the title compound (6 mg,3%). (400 MHz, DMSO-d₆) δ 8.23 (s, 2H), 7.92 (d, J=8.4 Hz, 1H),7.38-7.30 (m, 4H), 7.04 (t, J=8.3 Hz, 1H), 5.55 (d, J=11.0 Hz, 1H), 5.06(d, J=11.0 Hz, 1H), 4.78 (d, J=13.0 Hz, 2H), 3.96 (d, J=6.0 Hz, 2H),2.96 (t, J=12.5 Hz, 2H), 2.20 (m, 1H), 1.99 (d, J=12.3 Hz, 2H), 1.38 (m,2H).

Example B-35:6-(4-((1-(4-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A suspension of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole-3-oxidehydrochloride (0.25 g, 0.69 mmol), 2-chloro-4-ethylpyrimidine (0.12 g,0.83 mmol) and triethylamine (0.13 g, 1.04 mmol) in acetonitrile (10 mL)was heated under reflux overnight. The reaction mixture was cooled toambient temperature and evaporated in vacuo to form an oil which wastriturated with water (20 mL) to form a precipitate which was filteredoff and washed with cold methanol and dried to afford the title compoundas a light yellow powder (0.21 g, 65%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.21(d, J=4.9 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.70 (d, J=12.7 Hz, 1H), 7.63(s, 1H), 7.60-7.48 (m, 2H), 7.28 (t, J=8.8 Hz, 1H), 6.48 (d, J=4.9 Hz,1H), 5.64 (d, J=11.5 Hz, 1H), 5.22 (d, J=11.5 Hz, 1H), 4.75 (d, J=12.8Hz, 2H), 4.01 (d, J=6.5 Hz, 2H), 2.89 (t, J=12.8 Hz, 2H), 2.54 (q, J=7.6Hz, 2H), 2.18-2.02 (m, 1H), 1.85 (d, J=12.8 Hz, 2H), 1.31-1.17 (m, 5H).

Example B-36:4-((4-(Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine

To a solution of6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole-3-oxide(200 mg, 0.56 mmol) in tetrahydrofuran (20 mL) under argon atmospherewas added slowly a solution of borane-dimethylsulfide (BH₃*SMe₂) intetrahydrofuran (1.4 mL, 2.9 mmol) and the mixture was stirred at refluxfor 3 hours. The mixture was then cooled to ambient temperature andmethanol (2 mL) was added dropwise, and the resulting solution wasstirred at ambient temperature for 2 hours. The solvents were removedunder reduced pressure and the residue was triturated with saturatedaqueous solution of sodium bicarbonate. The formed precipitate wasfiltered off, washed with water and air-dried to give the title compound(110 mg, 57%) as a grey powder. [M+1]⁺ 344.

Example B-37:2-(4-((4-(Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-5-ethylpyrimidine

A solution of4-((4-((benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine(0.15 g, 0.43 mmol)), 2-chloro-5-ethylpyrimidine (0.08 g, 0.6 mmol) andtriethylamine (0.3 g, 3 mmol) in acetonitrile (30 mL) was stirred atreflux for 6 hours. Upon completion, the reaction mixture was allowed tocome to ambient temperature and a precipitate was formed, filtered offand washed sequentially with water and with hexanes. The crude productwas purified by column chromatography eluting with dichloromethane toobtain the title product (65 mg, 34%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.23 (s, 2H), 7.52 (d, J=13.1 Hz, 1H), 7.41 (d, J=8.2 Hz,1H), 7.33 (d, J=8.2 Hz, 1H), 7.24-7.13 (m, 3H), 5.80 (s, 2H), 4.66 (d,J=12.8 Hz, 2H), 3.96 (d, J=6.5 Hz, 2H), 2.88 (t, J=12.5 Hz, 2H), 2.42(q, J=7.6 Hz, 2H), 2.15-2.03 (bs, 1H), 1.84 (d, J=12.5 Hz, 2H),1.29-1.17 (m, 2H), 1.12 (t, J=7.6 Hz, 3H).

Example B-38:2-(4-((4-(Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-5-isopropylpyrimidine

A solution of4-((4-((benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine(0.15 g, 0.43 mmol)), 2-chloro-5-(1-methylethyl)pyrimidine (80 mg, 0.5mmol) and triethylamine (0.3 g, 3 mmol) in acetonitrile (30 mL) wasstirred at reflux for 6 hours. Upon completion, the reaction mixture wasallowed to cool to ambient temperature and a precipitate was formed,filtered off and washed sequentially with water and with hexanes. Thecrude product was purified by column chromatography eluting withdichloromethane to obtain the title product (57 mg, 27%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 2H), 7.52 (d, J=13.2 Hz,1H), 7.40 (d, J=8.1 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.24-7.16 (m, 3H),5.80 (s, 2H), 4.67 (d, J=13.0 Hz, 2H), 3.97 (d, J=6.4 Hz, 2H), 2.89 (t,J=12.0 Hz, 2H), 2.80-2.71 (m, 1H), 2.15-2.05 (bs, 1H), 1.84 (d, J=11.7Hz, 2H), 1.30-1.13 (m, 8H).

Example B-39:2-(4-((4-(Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-5-methoxpyrimidine

A suspension of4-((4-((benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine(155 mg, 0.45 mmol)), 2-chloro-5-methoxypyrimidine (78 mg, 0.54 mmol)and diisopropylethylamine (87 mg, 0.68 mmol) in acetonitrile (10 mL) wasstirred at reflux overnight. Upon cooling, the reaction mixture wasallowed to cool to ambient temperature and the solvent was removed invacuo and the crude product was purified by column chromatographyeluting with hexanes: ethyl acetate (4:1) to obtain the title product(63 mg, 31%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s,2H), 7.52 (d, J=13.1 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.33 (d, J=8.2 Hz,1H), 7.24-7.16 (m, 3H), 5.80 (s, 2H), 4.58 (d, J=12.8 Hz, 2H), 3.96 (d,J=6.5 Hz, 2H), 3.76 (s, 3H), 2.87 (t, J=12.5 Hz, 2H), 2.15-2.03 (bs,1H), 1.83 (d, J=12.5 Hz, 2H), 1.29-1.17 (m, 2H).

Example B-40:1-(4-((4-(Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidin-1-yl)-3-methylbutan-1-one

To a solution of4-((4-((benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine(150 mg, 0.43 mmol) and triethylamine (300 mg, 3 mmol) in acetonitrile(30 mL) at ambient temperature was added 3-methylbutanoyl chloride (48mg, 4 mmol) and the resulting solution was stirred for 6 hours. Aprecipitate was formed, filtered off and washed sequentially with waterand with hexanes. The crude product was purified by columnchromatography eluting with dichloromethane to obtain the title compoundas a white powder (50 mg, 38%). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.46-7.14(m, 3H), 7.14-6.85 (m, 3H), 5.75 (s, 2H), 5.01-4.43 (m, 1H), 4.20-3.71(m, 3H), 3.24-2.98 (m, 1H), 2.78-2.46 (m, 1H), 2.31-2.21 (m, 2H),2.20-2.06 (m, 2H), 2.05-1.94 (m, 1H), 1.94-1.80 (m, 1H), 1.30 (s, 2H),1.15-0.78 (m, 6H); [M+1]⁺ 435.5.

Example B-41:Tert-Butyl-(R)-4-((2-fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)phenoxy)methyl)Piperidine-1-carboxylate

To a solution oftert-butyl-4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy)methyl)piperidine-1-carboxylate (1.05 g, 2.4 mmol) in dioxane(20 mL) was added (R)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (0.73 g, 2.4 mmol) and cesium carbonate (1.0g, 3 mmol) and the reaction mixture was stirred at ambient temperaturefor 10 minutes. Then, it was purged with argon and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (0.1g, 0.1 mmol) was added at room temperature and the resultant solutionwas stirred for 1 hour and then heated at 60° C. for 2 hours. Aftercooling, the solvents were evaporated in vacuo and the residual oil waspurified by column chromatography on silica gel eluting withdichloromethane: ether mixture (1:1) to yield the title product (0.92 g,82%) as a white solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.92 (d, J=8.4 Hz,1H), 7.38-7.29 (m, 4H), 7.04 (t, J=8.6 Hz, 1H), 5.54 (d, J=11.1 Hz, 1H),5.06 (d, J=11.1 Hz, 1H), 4.19 (b s, 2H), 3.94 (d, J=6.5 Hz, 2H), 2.78(t, J=12.8 Hz, 2H), 2.10-2.00 (m, 1H), 1.87 (d, J=12.8 Hz, 2H), 1.48 (s,9H), 1.36-1.25 (m, 2H).

Example B-42:(R)-6-(3-Fluoro-4-(piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution oftert-butyl-(R)-4-((2-fluoro-4-(3-oxido-2H-benzo[d][1.3]oxathiol-6-yl)phenoxy)methyl)piperidine-1-carboxylate (910 mg, 1.97 mmol) in methylene chloride (30mL) was added trifluoroacetic acid (3.0 mL), and the reaction mixturewas stirred at ambient temperature for 10 minutes. The solvents wereremoved under reduced pressure and the residue was re-dissolved inacetonitrile (2 mL) and triturated with saturated aqueous sodiumbicarbonate (30 mL). A precipitate was formed, filtered off andair-dried to afford the title product (665 mg, 92%) as a white solid.LCMS [M+1]⁺ 362.1

Example B-43:Tert-Butyl-(S)-4-((2-fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)phenoxy)methyl)Piperidine-1-carboxylate

To a solution oftert-butyl-4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenoxy]methyl)piperidine-1-carboxylate (1.05 g, 2.4 mmol) in dioxane(20 mL) was added (S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (0.73 g, 2.4 mmol) and cesium carbonate (1.0g, 3 mmol) and the reaction mixture was stirred at ambient temperaturefor 10 minutes. Then, it was purged with argon and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (0.1g, 0.1 mmol) was added at room temperature and the resultant solutionwas stirred for 1 hour and then heated at 60° C. for 2 hours. Aftercooling, the solvents were evaporated in vacuo and the residual oil waspurified by column chromatography on silica gel eluting withdichloromethane: ether mixture (1:1) to yield the title product (0.92 g,82%) as a white solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.92 (d, J=8.4 Hz,1H), 7.38-7.29 (m, 4H), 7.04 (t, J=8.6 Hz, 1H), 5.54 (d, J=11.1 Hz, 1H),5.06 (d, J=11.1 Hz, 1H), 4.19 (b s, 2H), 3.94 (d, J=6.5 Hz, 2H), 2.78(t, J=12.8 Hz, 2H), 2.10-2.00 (m, 1H), 1.87 (d, J=12.8 Hz, 2H), 1.48 (s,9H), 1.36-1.25 (m, 2H).

Example B-44:(S)-6-(3-Fluoro-4-(piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution oftert-butyl-(S)-4-((2-fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)phenoxy]methyl}piperidine-1-carboxylate (910 mg, 1.97 mmol) in methylene chloride (30mL) was added trifluoroacetic acid (3.0 mL), and the reaction mixturewas stirred at ambient temperature for 10 minutes. The solvents wereremoved under reduced pressure and the residue was re-dissolved inacetonitrile (2 mL) and triturated with saturated aqueous sodiumbicarbonate (30 mL). A precipitate was formed, filtered off andair-dried to afford the title compound (665 mg, 92%) as a white solid.LCMS [M+1]⁺ 362.1

Example B-45:(S)-6-(4-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A solution of(S)-4-((2-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1.3]oxathiole3-oxide (0.27 g, 0.57 mmol)), 2-chloro-5-ethylpyrimidine (86 mg, 0.6mmol) and triethylamine (0.23 g, 2.3 mmol) in acetonitrile (50 mL) washeated at reflux for 6 hours. Upon cooling, a precipitate was formedwhich was filtered off and washed sequentially with water and withhexanes and further purified by column chromatography eluting withdichloromethane to give the title product (200 mg, 75%). ¹H NMR (400MHz, DMSO-d₆) δ 8.23 (s, 2H), 8.08 (d, J=7.9 Hz, 1H), 7.69 (d, J=12.8Hz, 1H), 7.62 (s, 1H), 7.59-7.49 (m, 2H), 7.28 (t, J=8.9 Hz, 1H), 5.64(d, J=11.0 Hz, 1H), 5.22 (d, J=11.0 Hz, 1H), 4.67 (d, J=12.7 Hz, 2H),4.01 (d, J=6.1 Hz, 2H), 2.89 (t, J=12.5 Hz, 2H), 2.46-2.39 (m, 2H),2.15-2.05 (bs, 1H), 1.84 (d, J=11.9 Hz, 2H), 1.31-1.19 (m, 2H), 1.13 (t,J=7.3 Hz, 3H).

Example B-46:(S)-6-(3-fluoro-4-((1-(5-isopropylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A solution of(S)-4-((2-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide (200 mg, 0.55 mmol), 2-chloro-5-isopropylpyrimidine (90 mg, 0.57mmol) and triethylamine (0.23 g, 2.3 mmol) in dimethylformamide (10 mL)was stirred at 50° C. for 3 hours. Upon cooling, the reaction mixturewas diluted with water (10 mL) a precipitate was formed which wasfiltered off and washed sequentially with water and with hexanes andfurther purified by column chromatography eluting with dichloromethaneto give the title product (210 mg, 81%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.27 (s, 2H), 8.07 (d, J=8.2 Hz, 1H), 7.70 (d, J=12.2Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H),7.27 (t, J=8.6 Hz, 1H), 5.64 (d, J=11.9 Hz, 1H), 5.22 (d, J=11.9 Hz,1H), 4.67 (d, J=12.8 Hz, 2H), 4.02 (d, J=5.7 Hz, 2H), 2.89 (t, J=12.5Hz, 2H), 2.80-2.72 (m, 1H), 2.15-2.05 (bs, 1H), 1.84 (d, J=12.3 Hz, 2H),1.31-1.20 (m, 2H), 1.18 (d, J=6.8 Hz, 6H).

Example B-47: 4-((4-Bromo-2-fluorophenoxy)methyl)piperidineHydrochloride

To a solution of tert-butyl4-[(4-bromo-2-fluorophenoxy)methyl]piperidine-1-carboxylate (ExampleB-7, 6.5 g, 16.7 mmol,) in dioxane (40 mL) was added 3M solution ofhydrogen chloride in dioxane (200 mL) and the mixture was stirred atambient temperature overnight. Ether (300 mL) was then slowly added toform a precipitate which was filtered off, washed with ether andair-dried to obtain the title compound (4.7 g, 87%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 9.01 (br.s, 1H), 8.67 (br.s, 1H), 7.53 (dd,J=11.0, 2.3 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.17 (t, J=9.0 Hz, 1H),3.94 (d, J=6.2 Hz, 2H), 3.27 (d, J=12.8 Hz, 2H), 2.88 (q, J=12.3 Hz,2H), 2.17-1.98 (m, 1H), 1.89 (d, J=12.5 Hz, 2H), 1.62-1.39 (m, 2H).

Example B-48:2-(4-((4-Bromo-2-fluorophenoxy)methyl)piperidin-1-yl)-5-methoxypyrimidine

To a solution of 4-((4-bromo-2-fluorophenoxy)methyl)piperidinehydrochloride (5.6 g, 17.3 mmol) in dimethylformamide (20 mL) was added2-chloro-5-methoxypyrimidine (2.7 g, 19.0 mmol) anddiisopropylethylamine (5.6 g, 43.3 mmol). The reaction mixture wasstirred and heated in “CEM” microwave system (140° C., 17 hours). Uponcompletion, the reaction mixture was poured into water (100 mL). Aprecipitate was filtered, air-dried and purified by columnchromatography eluting with hexanes: ethyl acetate mixture (9:1) toafford the title compound as a yellow solid (2.9 g, 42%). ¹H NMR (400MHz, DMSO-d₆) δ 8.18 (s, 2H), 7.51 (d, J=11.0 Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 7.14 (t, J=9.0 Hz, 1H), 4.56 (d, J=13.2 Hz, 2H), 3.98-3.88 (m,2H), 3.75 (s, 3H), 2.85 (t, J=12.7 Hz, 2H), 2.15-1.92 (m, 1H), 1.80 (d,J=13.2 Hz, 2H), 1.22 (dd, J=22.1, 9.6 Hz, 2H).

Example B-49:2-4-((2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)piperidin-1-yl)-5-methoxypyrimidine

To a solution of2-(4-((4-bromo-2-fluorophenoxy)methy)]piperidin-1-yl)-5-methoxypyrimidine(2.9 g, 7.3 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.8 g, 11.0mmol),) and potassium acetate (2.9 g, 29 mmol) in dioxane (15 mL) underargon atmosphere was added (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (0.54 g, 0.7 mmol) in dioxane (15 0mL) was added potassium acetate (2.9 g, 29 mmol) and the reactionmixture was stirred and heated to 95° C. overnight. Upon cooling, themixture was filtered through a pad of celite 545 and evaporated todryness. The product was purified by column chromatography on silica geleluting with hexanes: ethyl acetate mixture (5:1) to afford the titlecompound (1.9 g, 58%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.18 (s, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.33 (d, J=11.8 Hz, 1H), 7.17 (t,J=8.2 Hz, 1H), 4.57 (d, J=13.1 Hz, 2H), 3.96 (d, J=6.3 Hz, 2H), 3.76 (s,3H), 2.86 (t, J=12.2 Hz, 2H), 2.17-1.95 (m, 1H), 1.81 (d, J=11.9 Hz,2H), 1.36-1.13 (m, 14H).

Example B-50:(S)-6-(3-Fluoro-4-((1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of2-4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)piperidin-1-yl)-5-methoxypyrimidine (0.91 g, 2.1 mmol) indioxane (20 mL) was added (S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (0.62 g, 2.1 mmol), following by the additionof a solution of potassium carbonate (0.85 g, 6.3 mmol) in water (20 mL)and 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (105 mg, 0.14 mmol). The mixture was stirred and heated to85° C. for 2 hours and upon cooling, it was evaporated to give a residuewhich was taken up with water (60 mL) and ethyl acetate (100 mL). Theorganic phase was separated, washed with brine, dried over sodiumsulfate, filtered and the filtrate was evaporated to dryness. The crudeproduct was purified by column chromatography on silica gel eluting withhexanes: ethyl acetate mixture (1:1) to obtain the title compound (0.80g, 83%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 2H),8.07 (d, J=7.8 Hz, 1H), 7.69 (d, J=12.6 Hz, 1H), 7.62 (s, 1H), 7.59-7.49(m, 2H), 7.27 (t, J=8.5 Hz, 1H), 5.64 (d, J=11.3 Hz, 1H), 5.23 (d,J=11.3 Hz, 1H), 4.58 (d, J=13.2 Hz, 2H), 4.00 (d, J=6.3 Hz, 2H), 3.77(s, 3H), 2.87 (t, J=11.6 Hz, 2H), 2.14-2.04 (m, 1H), 1.83 (d, J=13.3 Hz,2H), 1.30-1.20 (m, 2H).

Example B-51:(R)-6-(3-Fluoro-4-((1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A solution of(R)-4-((2-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1.3]oxathiole3-oxide (150 mg, 0.41 mmol)), 2-chloro-5-methoxypyrimidine (72 mg, 0.49mmol) and triethylamine (63 mg, 0.60 mmol) in acetonitrile (20 mL) wasstirred at reflux for 6 hours. Upon cooling, a precipitate was formed,filtered off and washed sequentially with water and with hexanes. Thecrude product after washing was subjected to column chromatographyeluting with dichloromethane to obtain the title compound (58 mg, 30%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 2H), 8.07 (d,J=7.8 Hz, 1H), 7.69 (m, 1H), 7.63 (s, 1H), 7.49-7.59 (m, 2H), 7.28 (t,J=8.6 Hz, 1H), 5.63 (d, J=11.4 Hz, 1H), 5.24 (d, J=11.4 Hz, 1H), 4.56(d, J=13.2 Hz, 2H), 4.01 (d, J=6.4 Hz, 2H), 3.76 (s, 3H), 2.88 (t,J=11.6 Hz, 2H), 2.08 (m, 1H), 1.82 (d, J=13.3 Hz, 2H), 1.18-1.32 (m,2H).

Example B-52:(R)-6-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A solution of(R)-4-((2-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1.3]oxathiole3-oxide (150 mg, 0.41 mmol)), 2-chloro-5-ethylpyrimidine (72 mg, 0.49mmol) and triethylamine (63 mg, 0.60 mmol) in acetonitrile (20 mL) wasstirred at reflux for 6 hours. Upon cooling, a precipitate was formed,filtered off and washed sequentially with water and with hexanes. Thecrude product after washing was subjected to column chromatographyeluting with dichloromethane to obtain the title compound (78 mg, 40%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 2H), 8.08 (d,J=7.9 Hz, 1H), 7.69 (d, J=12.8 Hz, 1H), 7.62 (s, 1H), 7.59-7.49 (m, 2H),7.28 (t, J=8.9 Hz, 1H), 5.64 (d, J=11.0 Hz, 1H), 5.22 (d, J=11.0 Hz,1H), 4.67 (d, J=12.7 Hz, 2H), 4.01 (d, J=6.1 Hz, 2H), 2.89 (t, J=12.5Hz, 2H), 2.46-2.39 (m, 2H), 2.15-2.05 (b s, 1H), 1.84 (d, J=11.9 Hz,2H), 1.31-1.19 (m, 2H), 1.13 (t, J=7.3 Hz, 3H).

Example B-53:(R)-6-(3-fluoro-4-((1-(5-isopropylpyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A solution of(R)-4-((2-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1.3]oxathiole3-oxide (150 mg, 0.41 mmol)), 2-chloro-5-ethylpyrimidine (72 mg, 0.49mmol) and triethylamine (63 mg, 0.60 mmol) in acetonitrile (20 mL) wasstirred at reflux for 6 hours. Upon cooling, a precipitate was formed,filtered off and washed sequentially with water and with hexanes. Thecrude product after washing was subjected to column chromatographyeluting with dichloromethane to obtain the title compound (54 mg, 27%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 2H), 8.07 (d,J=8.2 Hz, 1H), 7.70 (d, J=12.2 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=8.2 Hz,1H), 7.51 (d, J=8.2 Hz, 1H), 7.27 (t, J=8.6 Hz, 1H), 5.64 (d, J=11.9 Hz,1H), 5.22 (d, J=11.9 Hz, 1H), 4.67 (d, J=12.8 Hz, 2H), 4.02 (d, J=5.7Hz, 2H), 2.89 (t, J=12.5 Hz, 2H), 2.80-2.72 (m, 1H), 2.15-2.05 (bs, 1H),1.84 (d, J=12.3 Hz, 2H), 1.31-1.20 (m, 2H), 1.18 (d, J=6.8 Hz, 6H).

Example B-54: tert-Butyl4-(((5-bromopyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate

To a mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(18.4 g, 85 mmol) and 5-bromo-2-chloropyrimidine (15.0 g, 77 mmol) intetrahydrofuran (200 mL) was added a suspension (60%) of sodium hydride(3.07 g, 128 mmol) in mineral oil and the resulting mixture was stirredunder argon at 70° C. for 16 hours. Upon completion ethanol (15 mL) wasslowly added to the reaction mixture and the reaction mixture wasdiluted with ethyl acetate (200 mL) and washed with brine (100 mL). Theorganic phase was separated, dried over magnesium sulfate, filtered andthe filtrate was evaporated under reduced pressure. The residue afterevaporation was subjected to column chromatography eluting withhexanes-ethyl acetate mixture 5:1 by volume to afford 15.13 g (52.4%) ofthe title compound as a white powder. The product was used in the nextstep without further purification.

Example B-55: tert-Butyl4-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(((5-bromopyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate (11.0 g,30 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxoborolane(7.5 g, 30 mmol) and 1,1′ (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (1.0 g, 1.3 mmol) and potassiumacetate (8.7 g, 09 mmol) in acetonitrile (300 mL) was stirred underargon at 70° C. for 16 hours. Upon cooling, the reaction mixture wasdiluted with ethyl acetate (200 mL) and washed with brine (100 mL). Theorganic phase was separated, dried over magnesium sulfate, filtered andthe filtrate was evaporated under reduced pressure. The residue afterevaporation was subjected to column chromatography eluting withhexanes-ethyl acetate mixture 8:1 by volume to afford the title compound(4.5 g, 36.4%) as a white powder. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (s,2H), 1.27 (m, 2H), 4.26 (s, J=6.7 Hz, 2H), 4.14 (m, 2H), 2.74 (t, J=12.9Hz, 2H), 2.02 (m, 1H), 1.84 (d, J=13.2 Hz, 2H), 1.46 (s, 9H), 1.35 (s,12H).

Example B-56: Tert-Butyl(R)-4-(((5-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate

A mixture tert-butyl4-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate(420 mg, 1 mmol), (R)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (300 mg, 1.0 mmol), potassium carbonate (820mg, 6.0 mmol) and 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium(II) Pd(dppf)Cl₂ (70 mg, 0.1 mmol) in water-dioxane (1:1) mixture (30mL) was stirred under argon at ambient temperature for 1 hour. Aprecipitate was formed, filtered off and purified by columnchromatography on silica gel eluting with dichloromethane to afford thecrude product which was further dissolved in dioxane (30 mL) and stirredwith Lewatit mono plus SP-112 resin (500 mg) for 2 hours. Afterfiltration the solvent was distilled off to afford the title product(445 mg, 99%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (s,2H), 8.16 (d, J=8.1 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.59 (dd, J=8.1,1.5 Hz, 1H), 5.67 (d, J=11.4 Hz, 1H), 5.24 (d, J=11.5 Hz, 1H), 4.24 (d,J=6.5 Hz, 2H), 3.99 (m, 2H), 2.74 (m, 2H), 1.99 (m, 1H), 1.73 (d, J=12.6Hz, 2H), 1.40 (s, 9H), 1.11-1.24 (br m, 2H).

Example B-57:(R)-6-(2-(Piperidin-4-ylmethoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of tert-butyl(R)-4-(((5-oxido-2H-benzo[d][1,3]oxathiol-6-yl]pyrimidin-2-yl}oxy)methyl)piperidine-1-carboxylate(445 mg, 1 mmol) in dichloromethane (50 mL) was added trifluoroaceticacid (25 mL). The mixture was stirred at ambient temperature for 7minutes. Then, the reaction mixture was evaporated to dryness and to theresidue was added a solution of saturated potassium carbonate. Aprecipitated was formed, filtered and air-dried to afford the titlecompound (340 mg, 99%). as a white solid: ¹H-NMR (400 MHz, CDCl₃) δ 8.74(s, 2H), 7.99 (d, J=8.1, 1H), 7.31-7.41 (m, 3H), 5.57 (d, J=10.9 Hz,1H), 5.08 (d, J=11.0 Hz, 1H), 4.28 (d, J=6.4 Hz, 2H), 3.17 (d, J=8.4 Hz,2H), 2.70 (m, 2H), 2.05 (m, 1H), 1.89 (d, J=13.1, 2H), 1.29-1.45 (br. m,2H).

Example B-58:(R)-6-(2-((1-(5-Chloropyridin-2-yl)piperidin-4-yl)methoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3-oxide

To a suspension of(R)-6-(2-(piperidin-4-ylmethoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3-oxide (346 mg, 1.0 mmol) and 2,5-dichloropyrimidine (193 mg, 1.3 mmol)in acetonitrile (20 mL) was added triethylamine (0.3 g, 3.0 mmol) andthe mixture was heated under reflux overnight. The solvent was removedunder reduced pressure and the residue was triturated with water. Asolid precipitate was formed, filtered off, washed with ether (10 mL)and air-dried to afford the title compound (50 mg, 11%) as a whitepowder. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 2H), 8.40 (s, 2H), 8.15 (d,J=7.9 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 5.65 (d, J=11.2 Hz,1H), 5.25 (d, J=11.2 Hz, 1H), 4.62 (d, J=12.5 Hz, 2H), 4.27 (d, J=56.0Hz, 2H), 2.95 (m, 2H), 2.15 (m, 1H), 2.15 (d, J=13.6 Hz, 2H), 1.17-1.32(br. m, 2H).

Example B-59:(S)-6-(4-((1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A solution of5-chloro-2-(4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl}piperidin-1-yl)pyrimidine(3.67 g, 14.9 mmol) was dissolved in a mixture of water:dioxane (150 mL,1:1) was added (S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (3.75 g, 12.4 mmol) followed by sodiumcarbonate (3.94 g, 37.2 mmol). The reaction mixture was purged withargon and 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II)Pd(dppf)Cl₂ (0.44 g, 0.6 mmol) was then slowly added and it was stirredat ambient temperature for 1 hour and then at 60° C. for 2 hours. Aftercooling, the solvent was evaporated in vacuo and the residue waspurified by column chromatography on silica gel, eluting with a mixtureof ethyl acetate: ether (1:1) to give the title product (3.8 g. 64.5%)as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 2H), 8.08 (d,J=8.1 Hz, 1H), 7.69 (d, J=12.9 Hz, 1H), 7.6-7.52 (m, 1H), 7.26 (t, J=8.6Hz, 1H), 5.64 (d, J=11.4 Hz, 1H), 5.23 (d, J=11.4 Hz, 1H), 4.62 (d,J=12.9 Hz, 2H), 4.01 (d, J 6.1 Hz, 2H), 2.98 (m, 2H), 2.13 (m, 1H), 1.86(d, J=12.2 Hz, 2H), 1.27 (m, 2H).

Example B-60:Tert-Butyl(S)-4-(((5-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate

A suspension of tert-butyl4-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate(420 mg, 1.0 mmol), (S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (0.3 g, 1.0 mmol), potassium carbonate (820mg, 6.0 mmol) and 1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium(II) Pd(dppf)Cl₂ (70 mg, 0.1 mmol) in a (30 mL) water-dioxane mixture(1:1) was stirred under argon at ambient temperature for 1 hour. Aprecipitate was formed, filtered off and purified by columnchromatography on silica gel eluting with dichloromethane to affordcrude product. This material was then dissolved in dioxane (30 mL) andstirred with Lewatit mono plus SP-112 resin (500 mg) for 2 hours. Afterfiltration, the solvents were distilled off to afford the title compound(445 mg, 99%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.01 (s,2H), 8.16 (d, J=8.1 Hz, 1H), 7.75 (d, J=1.22 Hz, 1H), 7.59 (dd, J=8.1,1.5 Hz, 1H), 5.67 (d, J=11.4 Hz, 1H), 5.24 (d, J=11.5 Hz, 1H), 4.24 (d,J=6.5 Hz, 2H), 3.99 (m, 2H), 2.74 (m, 2H), 1.99 (m, 1H), 1.73 (d, J=12.6Hz, 2H), 1.40 (s, 9H), 1.11-1.24 (br. m, 2H).

Example B-61:(S)-6-(2-(Piperidin-4-ylmethoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of tert-butyl(S)-4-((2-fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)pyrimidin-2-yl)oxy)methyl)piperidine-1-carboxylate(0.45 g, 1.0 mmol) in dichloromethane (50 mL) was treated withtrifluoroacetic acid (25 mL). The mixture was stirred at ambienttemperature for 10 minutes and then it was evaporated in vacuo. Theresidue was poured into an aqueous solution of saturated sodiumcarbonate. The solid material was filtered and air-dried to afford thetitle compound (0.34 g, 99%) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ8.74 (s, 2H), 7.99 (d, J=8.1 Hz, 1H), 7.31-7.41 (m, 3H), 5.57 (d, J=10.9Hz, 1H), 5.08 (d, J=11.0 Hz, 1H), 4.28 (d, J=6.4 Hz, 2H), 3.17 (d, J=8.4Hz, 2H), 2.70 (m, 2H), 2.05 (m, 1H), 1.89 (d, J=13.1 Hz, 2H), 1.29-1.45(br. m, 2H).

Example B-62:(S)-6-(2-((1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)methoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3-oxide

To a suspension of(S)-6-(2-piperidin-4-ylmethoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole3-oxide (346 mg, 1.0 mmol) and 2,5-dichloropyrimidine (193 mg, 1.3 mmol)in acetonitrile (20 mL) was added triethylamine (0.3 g, 3.0 mmol) andthe mixture was heated under reflux overnight. The solvent was removedunder reduced pressure and the residue was triturated with water. Asolid precipitate was formed, filtered off, washed with diethyl ether(10 mL) and air-dried to afford the title compound (15 mg, 3.3%) as awhite powder. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 2H), 8.40 (s, 2H),8.15 (d, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 5.65 (d,J=11.2 Hz, 1H), 5.25 (d, J=11.2 Hz, 1H), 4.62 (d, J=12.5 Hz, 2H), 4.27(d, J=6.0 Hz, 2H), 2.95 (m, 2H), 2.15 (m, 1H), 2.15 (d, J=13.6 Hz, 2H),1.17-1.32 (br. m, 2H).

Example B-63:Tert-Butyl-(R)-3-(methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.4 g, 2.0 mmol) andtriethylamine (0.55 mL, 4.0 mmol) in methylene chloride (15 mL) at 0° C.was dropwise added methanesulfonyl chloride (0.25 mL, 2.2 mmol). Thereaction mixture was stirred at ambient temperature for 4 hours and thenwashed sequentially with 0.1N hydrogen chloride and brine. The organiclayer was dried over Na₂SO₄ filtered, and concentrated in vacuo to yield2.5 g (90%) of the title product as an oil. [M+1]⁺ 280.

Example B-64: 6-(3-Fluoro-4-hydroxyphenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a suspension of 3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (3.1 g, 10.3 mmol),2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(2.4 g, 10.3 mmol) and 2M solution of sodium carbonate (16 mL, 30.9mmol) in dioxane (50 mL) was added slowly 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) (Pd(dppf)Cl₂ (375mg, 0.52 mmol) under argon. The mixture was stirred at 50° C. overnight,cooled to ambient temperature, and then dioxane was removed underreduced pressure. The residue was acidified with 1N HCl to pH 4 to forma precipitate which was filtered off, washed with water and air-dried togive 1.5 g (55%) of title compound as a brown powder. ¹H-NMR (400 MHz,DMSO-d₆).) δ 10.17 (br.s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.66-7.56 (m,2H), 7.50-7.41 (m, 2H), 7.05 (t, J=8.7 Hz, 1H), 5.64 (d, J=11.5 Hz, 1H),5.22 (d, J=11.5 Hz, 1H).

Example B-65: Tert-Butyl(3R)-3-((2-fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)phenoxy)methyl)pyrrolidine-1-carboxylate

To a stirred suspension of6-(3-fluoro-4-hydroxyphenyl)-2-benzo[d][1,3]oxathiole 3-oxide (525 mg,2.0 mmol) and potassium carbonate (550 mg, 4.0 mmol) indimethylformamide (20 mL) was addedtert-butyl-(R)-3-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(555 mg, 2.0 mmol) and the mixture was heated at 100° C. overnight. Thereaction mixture was then cooled to ambient temperature, and thevolatile compounds were removed under reduced pressure. The residue waspurified by column chromatography on silica gel eluting with ethylacetate to afford the title compound (510 mg, 57%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) δ 8.08 (d, J=8.2 Hz, 1H), 7.71 (d, J=12.6 Hz,1H), 7.63 (s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.30(t, J=8.7 Hz, 1H), 5.64 (d, J=11.5 Hz, 1H), 5.23 (d, J=11.5 Hz, 1H),4.17-4.04 (m, 2H), 3.56-3.06 (m, 4H), 2.75-2.59 (m, 1H), 2.09-1.95 (m,1H), 1.81-1.64 (m, 1H), 1.40 (s, 9H).

Example B-66:6-(3-Fluoro-4(((R)-pyrrolidin-3-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

Trifluoroacetic acid ((3 mL) was added to a solution of tert-butyl(3R)-3-([2-fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol-6-yl)phenoxy)methyl)pyrrolidine-1-carboxylate (200 mg, 0.4 mmol) in dichloromethane (10 mL)and the mixture was stirred at ambient temperature for 10 minutes. Thesolvents were removed under reduced pressure and the residue wastriturated with 10% aqueous solution of sodium bicarbonate. Aprecipitate was formed, filtered off and air-dried to afford the titleproduct as a white solid (155 mg, 98%). H-NMR (400 MHz, DMSO-d₆) δ 8.08(d, J=8.2 Hz, 1H), 7.71 (d, J=12.6 Hz, 1H), 7.63 (s, 1H), 7.57 (d, J=8.7Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.30 (t, J=8.7 Hz, 1H), 5.64 (d, J=11.5Hz, 1H), 5.23 (d, J=11.5 Hz, 1H), 4.13-3.94 (m, 2H), 3.37-2.66 (m, 5H),2.05-1.77 (m, 1H), 1.72-1.35 (m, 1H)

Example B-67:6-(4-(((R)-1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

A suspension of6-(3-fluoro-4-(((R)-pyrrolidin-3-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide (155 mg, 0.45 mmol) and 2-chloro-5-ethylpyrimidine (76 mg, 0.54mmol) and triethylamine (87 mg, 0.67 mmol) in acetonitrile (10 mL) washeated under reflux overnight. The volatile compounds were removed underreduced pressure and the residue was triturated with water (20 mL). Asolid was formed, filtered off, washed with methanol (10 mL) andair-dried to afford the title compound (138 mg, 68%) as a light yellowpowder. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 2H), 8.08 (d, J=8.2 Hz,1H), 7.71 (d, J=12.6 Hz, 1H), 7.63 (s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.52(d, J=8.2 Hz, 1H), 7.31 (t, J=8.7 Hz, 1H), 5.64 (d, J=11.5 Hz, 1H), 5.22(d, J=11.5 Hz, 1H), 4.21-4.09 (m, 2H), 3.77-3.58 (m, 2H), 3.53-3.35 (m,2H), 2.87-2.73 (m, 1H), 2.41 (q, J=7.5 Hz, 2H), 2.22-2.11 (m, 1H),1.94-1.80 (m, 1H), 1.12 (t, J=7.5 Hz, 3H).

Example B-68:(R)-3-((4-Benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)pyrrolidine

To a solution of6-fluoro-4-(((R)-pyrrolidin-3-yl)methoxy)phenyl-2H-benzo[d][1,3]oxathiole3-oxide (200 mg, 0.58 mmol) in tetrahydrofuran (20 mL) under argonatmosphere was added a solution of borane-dimethylsulfide (BH₃*SMe₂) intetrahydrofuran (1.4 mL, 2.9 mmol) and the mixture was stirred at refluxfor 3 hours. After the reaction was complete, the mixture was cooled toambient temperature and methanol (2 mL) was added dropwise, and theresulting mixture was stirred at ambient temperature for 2 hours. Thesolvents were then removed under reduced pressure and the residue wastriturated with saturated aqueous solution of sodium bicarbonate to forma precipitate which was filtered off, washed with water and air-dried togive the title compound (110 mg, 57%) as a grey powder. [M+1]⁺ 332

Example B-69:(R)-2-(3-((4-benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-5-ethylpyrimidine

To a suspension of(R)-3-((4-benzo[d][1.3]oxathiol-6-yl)-2-fluorophenoxy]methyl}pyrrolidine(134 mg, 0.40 mmol) and 2-chloro-5-ethylpyrimidine (69 mg, 0.48 mmol) inacetonitrile (10 mL) was added triethylamine (78 mg, 0.60 mmol) and themixture was heated under reflux overnight. The volatile compounds wereremoved under reduced pressure and the residue was purified by columnchromatography on silica gel eluting with chloroform: methanol mixture(40:1) to give the title compound as a white powder (62 mg, 35%). ¹H-NMR(400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.53 (d, J=12.7 Hz, 1H), 7.41 (d,J=8.6 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.28-7.16 (m, 3H), 5.80 (s, 1H),4.20-4.06 (m, 2H), 3.75-3.58 (m, 2H), 3.53-3.33 (m, 2H), 2.84-2.72 (m,1H), 2.42 (q, J=7.5 Hz, 2H), 2.21-2.10 (m, 1H), 1.92-1.80 (m, 1H), 1.12(t, J=7.5 Hz, 3H).

Example B-70:Tert-Butyl-(S)-3-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 9.9 mmol) andtriethylamine (2.8 mL, 19.8 mmol) in methylene chloride (50.0 mL) at 0°C. was dropwise added methanesulfonyl chloride (0.85 mL, 10.9 mmol). Thereaction mixture was stirred at ambient temperature for 4 hours and thenwashed sequentially with 0.1 N hydrogen chloride and brine. The organiclayer was dried over Na₂SO₄ filtered, and concentrated in vacuo to yield2.5 g (90%) of the title product as an oil. [M+1]⁺ 280.

Example B-71:Tert-Butyl-(S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

A solution oftert-butyl-(S)-3-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(2.2 g, 7.9 mmol), 4-bromo-2-fluorophenol (1.8 g, 9.5 mmol) andpotassium carbonate (2.2 g, 15.8 mmol) in dimethylformamide (100 mL) wasstirred at 100° C. overnight. After cooling to ambient temperature, thesolvent was removed under reduced pressure. The residue was treated withacetonitrile (100 mL) and the resultant suspension was filtered througha pad of celite. The filtrate was evaporated to dryness and the residuewas treated with water (50 mL). The mixture was extracted with ethylacetate (2×50 mL), dried over sodium sulfate and filtered. The filtratewas evaporated, and purified by chromatography on a silica gel pad (3cm) eluting with a mixture of hexanes: ethyl acetate (4:1) to give thetitle product (2.9 g, 98%) as alight yellow oil. ¹H-NMR (400 MHz,DMSO-d₆,) δ 7.52 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.16 (t,J=8.7 Hz, 1H), 4.08-3.96 (m, 2H), 3.56-3.06 (m, 4H), 2.75-2.59 (m, 1H),2.09-1.95 (m, 1H), 1.81-1.64 (m, 1H), 1.40 (s, 9H).

Example B-72: (S)-3-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidineHydrochloride

To a stirred solution oftert-butyl-(S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate(2.9 g, 7.7 mmol) in dioxane (30 mL) was added 3M solution of hydrogenchloride in dioxane (10 mL) and the mixture was stirred at 40° C.overnight. Upon completion dioxane was evaporated to the residual volumeof 10 mL, and diethyl ether (150 mL) was added. A precipitate wasformed, stirred for 20 minutes then, filtered off and air-dried to givethe title product (1.7 g, 71%). as a white powder. ¹H-NMR (400 MHz,DMSO-d₆,) δ 9.48 (br.s, 2H), 7.52 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.7 Hz,1H), 7.16 (t, J=8.7 Hz, 1H), 4.15-4.03 (m, 2H), 3.40-3.10 (m, 3H),3.03-2.94 (m, 1H), 2.80-2.66 (m, 1H), 2.15-2.02 (m, 1H), 1.81-1.67 (m,1H).

Example B-73:(S)-2-(3-((4-Bromo-2-fluorophenoxy)methyl]pyrrolidin-1-yl)-5-ethylpyrimidine

A mixture of (S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidinehydrochloride (1.70 g, 5.5 mmol), 2-chloro-5-ethylpyrimidine (0.85 g,6.1 mmol) and diisopropylethylamine (1.77 g, 13.8 mmol) indimethylformamide (150 mL) was stirred at 130° C. overnight. Aftercooling to ambient temperature, dimethylformamide was removed underreduced pressure and the residue was treated with water (200 mL). Abrown precipitate was formed which was filtered and re-dissolved inmethylene chloride until the solution was clear. This was then driedover sodium sulfate, and filtered through a 3 cm silica gel pad. Thesolution was then evaporated in vacuo and the residue was purified bycolumn chromatography by eluting with hexanes-ethyl acetate mixture(4:1) to obtain the title product (1.3 g, 62%) as colorless crystals.¹H-NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.52 (d, J=8.7 Hz, 1H), 7.32(d, J=8.7 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 4.17-4.02 (m, 2H), 3.77-3.58(m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.41 (q, J=7.5 Hz, 2H),2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.12 (t, J=7.5 Hz, 3H).

Example B-74:(S)-5-Ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl]pyrrolidin-1-yl)pyrimidine

To a solution of(S)-2-(3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-5-ethylpyrimidine(1.3 g, 3.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.0 g, 4.1mmol), and potassium acetate (1.3 g, 12 mmol) in dioxane (50 mL) underargon atmosphere was added (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (170 mg, 0.2 mmol) and the mixturewas heated to 85° C. and stirred at that temperature overnight. Themixture was cooled and filtered through a pad of celite. The celite padwas washed with hot (50° C.) dioxane (100 mL) and the washings werecombined with the filtrate and evaporated to dryness. The residue wassubjected to column chromatography eluting with ether to obtain thecrude product as a light yellow oil. This oil was dissolved in hexanes(100 mL) and placed into freezer for three days. White crystals wereformed, filtered off and dried to afford the title compound (0.83 g,56%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.43 (d, J=8.7 Hz, 1H),7.34 (d, J=8.7 Hz, 1H), 7.21 (t, J=8.7 Hz, 1H), 4.19-4.05 (m, 2H),3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.41 (q, J=7.5Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.16 (s, 12H), 1.12 (t,J=7.5 Hz, 3H).

Example B-75:(S)-6-(4-(((S)-1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)methoxy)-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide

To a solution of (S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (112 mg, 0.37 mmol) and(S)-5-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl]pyrrolidin-1-yl}pyrimidine(158 mg, 0.37 mmol) in dioxane (2.5 mL) was added a solution ofpotassium carbonate (153 mg, 1.11 mmol) in water (2.5 mL). Afterstirring under argon atmosphere for 10 minutes, 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (19mg, 0.03 mmol) was added then the reaction mixture was stirred atambient temperature Water (30 mL) was then added and a grey precipitatewas formed, filtered off and air-dried. The precipitate was purified bycolumn chromatography eluting with ethyl acetate to give the titlecompound as a white powder (24 mg, 15%). H-NMR (400, MHz, DMSO-d₆) δ8.22 (s, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.71 (d, J=12.6 Hz, 1H), 7.63 (s,1H), 7.57 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.31 (t, J=8.7 Hz,1H), 5.64 (d, J=11.5 Hz, 1H), 5.22 (d, J=11.5 Hz, 1H), 4.21-4.09 (m,2H), 3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.41 (q,J=7.5 Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.12 (t, J=7.5 Hz,3H).

Example B-76:(R)-6-(4-(((S)-1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)methoxy-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide

To a solution of (R)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (121 mg, 0.40 mmol) and(S)-5-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine(171 mg, 0.40 mmol) in dioxane (3.0 mL) was added a solution ofpotassium carbonate (166 mg, 1.20 mmol) in water (3.0 mL). Afterstirring under argon atmosphere for 10 minutes, 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (21mg, 0.03 mmol) was added then the reaction mixture was stirred atambient temperature overnight. Water (30 mL) was then added and a greyprecipitate was formed, filtered off and air-dried. The precipitate waspurified by column chromatography eluting with ethyl acetate to give thetitle compound as a white powder (24 mg, 14%). ¹H-NMR (400 MHz, DMSO-d₆)δ 8.22 (s, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.71 (d, J=12.6 Hz, 1H), 7.63(s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.31 (t, J=8.7Hz, 1H), 5.64 (d, J=11.5 Hz, 1H), 5.22 (d, J=11.5 Hz, 1H), 4.21-4.09 (m,2H), 3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.41 (q,J=7.5 Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.12 (t, J=7.5 Hz,3H).

Example B-77:(S)-6-(4-(((R)-1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)methoxy-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide

To a solution of (S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (112 mg, 0.37 mmol) and(R)-5-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine(158 mg, 0.37 mmol) in dioxane (2.5 mL) was added a solution ofpotassium carbonate (153 mg, 1.11 mmol) in water (2.5 mL). Afterstirring under argon atmosphere for 10 minutes, 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (19mg, 0.03 mmol) was added then the reaction mixture was stirred atambient temperature overnight. Water (30 mL) was then added and a greyprecipitate was formed, filtered off and air-dried. The precipitate waspurified by column chromatography eluting with ethyl acetate to give thetitle compound as a white powder (25 mg, 15%). ¹H-NMR (400, MHz,DMSO-d₆) δ 8.22 (s, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.71 (d, J=12.6 Hz,1H), 7.63 (s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.31(t, J=8.7 Hz, 1H), 5.64 (d, J=11.5 Hz, 1H), 5.22 (d, J=11.5 Hz, 1H),4.21-4.09 (m, 2H), 3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m,1H), 2.41 (q, J=7.5 Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.12(t, J=7.5 Hz, 3H).

Example B-78:(R)-6-(4-(((R)-1-(5-Ethylpyrimidin-2-yl)pyrrolidin-3-yl)methoxy-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide

To a solution of (R)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (112 mg, 0.37 mmol) and(R)-5-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl]pyrrolidin-1-yl)pyrimidine(158 mg, 0.37 mmol) in dioxane (2.5 mL) was added a solution ofpotassium carbonate (153 mg, 1.11 mmol) in water (2.5 mL). Afterstirring under argon atmosphere for 10 minutes, 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (19mg, 0.03 mmol) was added then the reaction mixture was stirred atambient temperature overnight. Water (30 mL) was then added and a greyprecipitate was formed, filtered off and air-dried. The precipitate waspurified by column chromatography eluting with ethyl acetate to give thetitle compound as a white powder (25 mg, 15%). ¹H-NMR (400, MHz,DMSO-d₆) δ 8.22 (s, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.71 (d, J=12.6 Hz,1H), 7.63 (s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.31(t, J=8.7 Hz, 1H), 5.64 (d, J=11.5 Hz, 1H), 5.22 (d, J=11.5 Hz, 1H),4.21-4.09 (m, 2H), 3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m,1H), 2.41 (q, J=7.5 Hz, 2H), 2.22-2.11 (m, 1H), 1.94-1.80 (m, 1H), 1.12(t, J=7.5 Hz, 3H).

Example B-79:(S)-2-(3-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-5-chloropyrimidine

A solution of (S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidinehydrochloride (4.09 g, 13.2 mmol), 2,5-dichloropyrimidine (1.0 g, 7.1mmol) and triethylamine (4.0 g, 39.6 mmol) in dimethylacetamide (15 mL)was stirred and heated in CEM microwave system (150° C., 3 hours). Aftercooling to ambient temperature, dimethylacetamide was removed underreduced pressure and the residue was treated with water and extractedwith ethyl acetate (3×50 mL). The combined organic extracts were washed5% citric acid, sodium bicarbonate solution, brine and then dried oversodium sulfate, and filtered. The solution was then evaporated in vacuoand the residue was purified by column chromatography by eluting withhexanes: ethyl acetate mixture (1:1) to afford the title product (4.5 g,88%) as a colorless oil.

Example B-80:(S)-5-Chloro-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine

To a solution of(S)-2-(3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl}-5-chloropyrimidine(4.50 g, 11.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.0 g, 4.1mmol),) and potassium acetate (4.55 g, 45.2 mmol) in dioxane (120 mL)under argon atmosphere was added 1,1′ (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (878 mg, 1.2 mmol) and the mixturewas heated to 90° C. and stirred at that temperature overnight. Themixture was cooled and poured into a solution of ethyl acetate and water(100 mL: 100 mL) and filtered through a celite 545 pad (1 cm). Thecelite pad was washed with ethyl acetate and the washings were combinedwith the filtrate, dried over sodium sulfate and evaporated to dryness.The residue was subjected to column chromatography eluting with hexanes:ethyl acetate to obtain the title compound as a light yellow oil. (1.9g, 30%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.43 (d, J=8.7 Hz,1H), 7.34 (d, J=8.7 Hz, 1H), 7.21 (t, J=8.7 Hz, 1H), 4.19-4.05 (m, 2H),3.77-3.58 (m, 2H), 3.53-3.35 (m, 2H), 2.87-2.73 (m, 1H), 2.22-2.11 (m,1H), 1.94-1.80 (m, 1H), 1.16 (s, 12H).

Example B-81:(S)-6-(4-(((S)-1-(5-Chloropyrimidin-2-yl)pyrrolidin-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of(S)-5-chloro-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine(300 mg, 0.7 mmol) in dioxane (15 mL) was added(S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (212mg, 0.7 mmol), 2M aqueous solution of sodium carbonate (15 mL) and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (73mg, 0.1 mmol). The mixture was stirred with heating to 85° C. for 3hours and then at ambient temperature overnight. To the mixture was thenadded water (50 mL) and the organic phase was extracted with ethylacetate (3×30 mL). The combined extracts were washed with water, brine,dried over magnesium sulfate, filtered and the filtrate was evaporated.The product was purified by column chromatography on silica gel elutingwith hexanes: ethyl acetate mixture (1:1) to afford the title product(112 mg, 37.2%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s,2H), 8.08 (d, J=8.1 Hz, 1H), 7.71 (d, J=12.8 Hz, 1H), 7.63 (s, 1H), 7.57(d, J=8.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.31 (t, J=8.8 Hz, 1H), 5.64(d, J=11.4 Hz, 1H), 5.23 (d, J=11.4 Hz, 1H), 4.33-3.99 (m, 2H),3.82-3.58 (m, 2H), 3.57-3.44 (m, 1H), 3.42-3.34 (m, 1H), 2.98-2.69 (m,1H), 2.30-2.06 (m, 1H), 2.01-1.76 (m, 1H).

Example B-82:(S)-2-(3-((4-Bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl)-4-ethylpyrimidine

A solution of (S)-3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidinehydrochloride (2.0 g, 6.4 mmol), 2-chloro-4-ethylpyrimidine (1.0 g, 7.0mmol) and diisopropylethylamine (1.7 g, 12.8 mmol) in dimethylacetamide(10 mL) was stirred and heated in CEM microwave system (150° C., 3hours). After cooling to ambient temperature, dimethylacetamide wasremoved under reduced pressure and the residue was treated with waterand extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with 5% citric acid, sodium bicarbonate solution,brine and then dried over sodium sulfate, and filtered. The solution wasthen evaporated in vacuo and the residue was purified by columnchromatography by eluting with hexanes:ethyl acetate mixture (1:1) toafford the title compound (1.8 g, 74%) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 8.21 (d, J=5.0 Hz, 1H), 7.26-7.10 (m, 2H), 6.85 (t, J=8.7Hz, 1H), 6.40 (d, J=5.1 Hz, 1H), 4.04 (d, J=6.9 Hz, 2H), 3.95-3.70 (m,2H), 3.69-3.56 (m, 1H), 3.49 (dd, J=11.3, 6.6 Hz, 1H), 2.93-2.76 (m,1H), 2.62 (q, J=7.6 Hz, 2H), 2.33-2.15 (m, 1H), 2.04-1.87 (m, 1H), 1.27(t, J=7.6 Hz, 3H).

Example B-83:(S)-4-Ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl]pyrrolidin-1-yl)pyrimidine

To a solution of(S)-2-(3-((4-bromo-2-fluorophenoxy)methyl)pyrrolidin-1-yl}-4-ethylpyrimidine(1.8 g, 4.7 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.4 g, 5.6mmol),) and potassium acetate (1.9 g, 18.8 mmol) in dioxane (120 mL)under argon atmosphere was added 1,1′ (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (220 mg, 0.3 mmol) and the mixturewas heated to 90° C. and stirred at that temperature overnight. Themixture was cooled and poured into a solution of ethyl acetate and water(100 mL: 100 mL) and filtered through a celite 545 pad (1 cm). Thecelite pad was washed with ethyl acetate and the washings were combinedwith the filtrate, dried over sodium sulfate and evaporated to dryness.The residue was subjected to column chromatography eluting with hexanes:ethyl acetate (2:1) to obtain the title compound as a light yellow oil.(1.9 g, 94%). H NMR (400 MHz, CDCl₃) δ 8.20 (d, J=5.1 Hz, 1H), 7.56-7.45(m, 2H), 6.95 (t, J=8.2 Hz, 1H), 6.38 (d, J=5.1 Hz, 1H), 4.08 (d, J=6.9Hz, 2H), 3.89 (dd, J=11.3, 7.4 Hz, 1H), 3.82-3.72 (m, 1H), 3.68-3.57 (m,1H), 3.49 (dd, J=11.4, 6.7 Hz, 1H), 2.94-2.80 (m, 1H), 2.61 (q, J=7.6Hz, 2H), 2.32-2.20 (m, 1H), 2.00-1.89 (m, 1H), 1.34 (s, 12H), 1.25 (t,J=7.6 Hz, 3H).

Example B-84:(S)-6-(4-(((S)-1-(4-Ethylpyrimidin-2-yl)pyrrolidine-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of(S)-4-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl]pyrrolidin-1-yl}pyrimidine(311 mg, 0.73 mmol) in dioxane (15 mL) was added(S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (220mg, 0.73 mmol), 2M aqueous solution of sodium carbonate (1.1 mL) and1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂(27 mg, 0.04 mmol). The mixture was stirred and heated at 40° C.overnight. Upon cooling, water was added water (50 mL) and the mixturewas extracted with ethyl acetate (3×30 mL). The combined organicextracts were washed with water, brine, dried over Na₂SO₄, filtered andthe filtrate was evaporated to dryness. The residue after evaporationwas purified to column chromatography on silica gel eluting hexanes:ethyl acetate mixture (1:1) to afford the title compound (73 mg, 22%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=4.9 Hz, 1H), 8.08(d, J=8.1 Hz, 1H), 7.77-7.43 (m, 4H), 7.32 (t, J=8.8 Hz, 1H), 6.49 (d,J=4.9 Hz, 1H), 5.65 (d, J=11.4 Hz, 1H), 5.23 (d, J=11.4 Hz, 1H),4.26-4.05 (m, 2H), 3.81-3.59 (m, 2H), 3.57-3.33 (m, 2H), 2.88-2.70 (m,1H), 2.55 (q, J=7.5 Hz, 2H), 2.23-2.07 (m, 1H), 1.95-1.77 (m, 1H), 1.17(t, J=7.5 Hz, 3H).

Example B-85:(R)-6-(4-(((S)-1-(4-Ethylpyrimidin-2-yl)pyrrolidine-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of(S)-4-ethyl-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl]pyrrolidin-1-yl}pyrimidine(311 mg, 0.73 mmol) in dioxane (15 mL) was added(R)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (220mg, 0.73 mmol), 2M aqueous solution of sodium carbonate (1.1 mL) and1,1′ (bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂(27 mg, 0.04 mmol. The mixture was stirred and heated at 40° C.overnight. Upon cooling, water was added water (50 mL) and the mixturewas extracted with ethyl acetate (3×30 mL). The combined organicextracts were washed with water, brine, dried over Na₂SO₄, filtered andthe filtrate was evaporated to dryness. The residue after evaporationwas purified to column chromatography on silica gel eluting hexanes:ethyl acetate mixture (1:1) to afford the title compound (127 mg, 38%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=4.9 Hz, 1H),8.08 (d, J=8.1 Hz, 1H), 7.77-7.43 (m, 4H), 7.32 (t, J=8.8 Hz, 1H), 6.49(d, J=4.9 Hz, 1H), 5.65 (d, J=11.4 Hz, 1H), 5.23 (d, J=11.4 Hz, 1H),4.26-4.05 (m, 2H), 3.81-3.59 (m, 2H), 3.57-3.33 (m, 2H), 2.88-2.70 (m,1H), 2.55 (q, J=7.5 Hz, 2H), 2.23-2.07 (m, 1H), 1.95-1.77 (m, 1H), 1.17(t, J=7.5 Hz, 3H).

Example B-86:(R)-6-(4-(((S)-1-(5-Chloropyrimidin-2-yl)pyrrolidine-3-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution of(S)-5-chloro-2-(3-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl]pyrrolidin-1-yl}pyrimidine(300 mg, 0.7 mmol) in dioxane (15 mL) was added(R)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yl trifluoromethanesulfonate (212mg, 0.7 mmol), 2M aqueous solution of sodium carbonate (1.1 mL) and 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (73mg, 0.7 mmol). The mixture was stirred and heated at 85° C. for 3 hours.Upon cooling, water was added water (50 mL) and the mixture wasextracted with ethyl acetate (3×30 mL). The combined organic extractswere washed with water, brine, dried over Na₂SO₄, filtered and thefiltrate was evaporated to dryness. The residue after evaporation waspurified to column chromatography on silica gel eluting hexanes: ethylacetate mixture (1:1) to afford the title compound (100 mg, 31%) as awhite solid. ¹H NMR (300 MHz, DMSO) δ 8.40 (s, 2H), 8.08 (d, J=8.1 Hz,1H), 7.71 (d, J=12.8 Hz, 1H), 7.63 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.52(d, J=8.1 Hz, 1H), 7.31 (t, J=8.8 Hz, 1H), 5.64 (d, J=11.4 Hz, 1H), 5.23(d, J=11.4 Hz, 1H), 4.33-3.99 (m, 2H), 3.82-3.58 (m, 2H), 3.57-3.44 (m,1H), 3.42-3.34 (m, 1H), 2.98-2.69 (m, 1H), 2.30-2.06 (m, 1H), 2.01-1.76(m, 1H).

Example B-87: tert-Butyl(S)-3-((4-bromophenoxy)methyl)pyrrolidine-1-carboxylate

A solution containing tert-butyl(S)-3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (2.7 g, 9.7mmol), 4-bromophenol (2.0 g, 11.6 mmol) and potassium carbonate (4.0 g,29.1 mmol) in dimethylformamide (100 mL) was stirred at 100° C.overnight. After cooling to ambient temperature the solvent was removedunder reduced pressure and the residue was treated with acetonitrile(100 mL) and then was filtered through a pad of celite. The filtrate wasevaporated to dryness then treated with water (50 mL) and extracted withethyl acetate (2×50 mL), dried over sodium sulfate, filtered and thefiltrate was evaporated. The residue was purified by columnchromatography on a silica gel pad (3 cm) eluting with a mixture ofhexanes: ethyl acetate (4:1) to afford the title product (3.2 g, 93%) asa light yellow liquid. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.44 (d, J=8.6 Hz,2H), 6.92 (d, J=8.8 Hz, 2H), 4.01-3.86 (m, 2H), 3.50-3.34 (m, 2H),3.29-3.15 (m, 1H), 3.11-3.01 (m, 1H), 2.68-2.54 (m, 1H), 2.08-1.88 (m,1H), 1.79-1.59 (m, 1H), 1.39 (s, 9H).

Example B-88: (S)-3-((4-Bromophenoxy)methyl)pyrrolidine Hydrochloride

To a solution of tert-butyl(S)-3-((4-bromophenoxy)methyl)pyrrolidine-1-carboxylate (3.2 g, 9.0mmol) in dioxane (30 mL) was added 3M solution of hydrogen chloride indioxane (10 mL) and the mixture was stirred with heating at 40° C.overnight. Dioxane was evaporated to a residual volume of about 10 mL,and the residue was triturated with diethyl ether (150 mL). Aprecipitate was formed and stirred for 20 minutes then filtered off andair-dried to give the title compound (2.3 g, 87%). as a white powder.¹H-NMR (400 MHz, DMSO-d₆) δ 9.29 (br.s, 2H), 7.46 (d, J=9.0 Hz, 2H),6.93 (d, J=9.0 Hz, 2H), 4.06-3.92 (m, 2H), 3.32-3.07 (m, 3H), 3.06-2.92(m, 1H), 2.77-2.63 (m, 1H), 2.18-1.98 (m, 1H), 1.83-1.64 (m, 1H).

Example B-89:(S)-2-(3-((4-Bromophenoxy)methyl)pyrrolidin-1-yl)-5-ethylpyrimidine

A mixture of (S)-3-((4-bromophenoxy)methyl)pyrrolidine hydrochloride(1.15 g, 3.9 mmol), 2-chloro-5-ethylpyrimidine (0.62 g, 4.3 mmol) anddiisopropylethylamine (1.27 g, 9.7 mmol) in dimethylformamide (50 mL)was stirred at 130° C. overnight. After cooling to ambient temperature,dimethylformamide was removed under reduced pressure and the residue wastreated with water (200 mL). A brown precipitate was formed and then themother liquor was decanted. The precipitate was re-dissolved indichloromethane, dried over sodium sulfate and purified on a 3 cm silicagel pad eluted with hexanes: ethyl acetate mixture gradient (4:1 to 2:1)to afford the title product (0.73 g, 51%) as colorless powder. ¹H-NMR(400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 7.44 (d, J=9.0 Hz, 2H), 6.94 (d,J=9.0 Hz, 2H), 4.12-3.87 (m, 2H), 3.75-3.55 (m, 2H), 3.52-3.39 (m, 1H),3.37-3.26 (m, 1H), 2.79-2.64 (m, 1H), 2.41 (q, J=7.5 Hz, 2H), 2.20-2.05(m, 1H), 1.91-1.75 (m, 1H), 1.11 (t, J=7.6 Hz, 3H).

Example B-90:(S)-5-Ethyl-2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine

To a solution of(S)-2-(3-((4-bromophenoxy)methyl)pyrrolidin-1-yl)-5-ethylpyrimidine (900mg, 2.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (950 mg, 3.8mmol),) and potassium acetate (970 mg, 10 mmol) in dioxane (50 mL) underargon atmosphere was added 1,1′ (bisdiphenylphosphino)ferrocenedichloropalladium (II) Pd(dppf)Cl₂ (0.18 g, 0.25 mmol) and the mixturewas heated to 85° C. overnight. After cooling, it was filtered through apad of celite, then washed with hot (50° C.) dioxane (100 mL). Thefiltrate was evaporated to dryness and the residue was adsorbed on asilica gel column and eluted with ether to obtain the crude product as alight yellow oil. This oil was used in the next step withoutpurification. LCMS [M+1]⁺ 410

Example B-91:(S)-6-(4-(((S)-1-(5-Ethylpyrimidin-2-yl)pyrrolidine-3-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole3-oxide

To a solution containing (S)-3-oxido-2H-benzo[d][1,3]oxathiol-6-yltrifluoromethanesulfonate (150 mg, 0.50 mmol), 2M aqueous solution ofsodium carbonate (1.1 mL) and(S)-5-ethyl-2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine(203 mg, 0.50 mmol) in dioxane (3 mL) was added 1,1′(bisdiphenylphosphino)ferrocene dichloropalladium (II) Pd(dppf)Cl₂ (25mg, 0.035 mmol) under an argon atmosphere and then stirred at ambienttemperature overnight. Water (30 mL) was then added and a greyprecipitate was formed, filtered off and air-dried. The precipitate waspurified by column chromatography eluting with ethyl acetate to give thetitle compound (100 mg, 46%) as a white powder. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.22 (s, 2H), 8.07 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.2 Hz, 2H),7.57 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 5.64 (d,J=11.2 Hz, 1H), 5.22 (d, J=11.2 Hz, 1H), 4.18-3.97 (m, 2H), 3.78-3.56(m, 2H), 3.54-3.41 (m, 1H), 3.40-3.34 (m, 1H), 2.85-2.67 (m, 1H), 2.42(q, J=7.6 Hz, 2H), 2.23-2.06 (m, 1H), 1.96-1.78 (m, 1H), 1.12 (t, J=7.6Hz, 3H).

Example C-1: 2-oxo-1,3-benzoxathiol-6-yl trifluoromethanesulfonate

Into a solution of 6-hydroxy-1,3-benzoxathiol-2-one (26.0 g, 155 mmol)in pyridine (250 mL) at 0° C. was slowly added triflic anhydride (52.3g, 185 mmol). The reaction mixture was stirred for 40 min at 0° C. andovernight at ambient temperature. The volatiles were distilled off underreduced pressure and the residue after evaporation was treated withethyl acetate (400 mL). The suspension was washed with 10% watersolution of citric acid (300 mL) followed by brine (300 mL) and water(500 mL). The organic layer was dried over magnesium sulfate andfiltered. The filtrate was evaporated under reduced pressure. A residueafter evaporation was washed with ether (250 mL) and was subjected tocolumn chromatography elution with dichloromethane to produce2-oxo-1,3-benzoxathiol-6-yl trifluoromethanesulfonate (40.1 g, 86%) as awhite powder. ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.97 (d, J=8.80 Hz, 1H), 7.91(d, J=2.45 Hz, 1H), 7.51 (dd, J=8.68, 2.45 Hz, 1H).

Example C-2: 3-hydroxy-4-mercaptophenyl Trifluoromethanesulfonate

A solution of 3-hydroxy-4-mercaptophenyl trifluoromethanesulfonate (40.1g, 133 mmol) in oxygen free 2N aqueous sodium hydroxide (250 mL) undernitrogen atmosphere was boiled for 1 h in a stream of oxygen-freenitrogen. The solution was allowed to cool under nitrogen to ambienttemperature and then was acidified with 2N aqueous sulfuric acid to pH6.5. The solution was saturated with sodium sulphate and extracted withether (2×450 mL). The combined extracts were concentrated under reducedpressure to afford the crude title product. The crude product was usedin the next step without further purification (20.1 g, 54.7%).

Example C-3: 2,2-dimethyl-1,3-benzoxathiol-6-ylTrifluoromethanesulfonate

To a solution of 3-hydroxy-4-mercaptophenyl trifluoromethanesulfonate(2.5 g, 9.1 mmol) in benzene (100 mL) were added acetone (5.3 g, 91mmol) and p-toluenesulfonic acid (173 mg, 0.9 mmol). The mixture wasstirred at reflux with Dean-Stark adapter for 7 days with TLC control.To the mixture was added ethyl acetate (100 mL) and a saturated aqueoussolution of sodium bicarbonate (50 mL). The organic layer was separatedand washed with brine, dried over sodium sulfate, filtered and thefiltrate was evaporated to dryness. The product was used in the nextstep without further purification. Brown oil (2.8 g, 100%).

Example C-4: 2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-6-ylTrifluoromethanesulfonate

To a solution of 2,2-dimethyl-1,3-benzoxathiol-6-yltrifluoromethanesulfonate (2.8 g, 9.1 mmol) in acetic acid (40 mL) wasadded 30% aqueous solution hydrogen peroxide (8 mL). The mixture wasstirred at −70° C. for 17 h. To the mixture was added ethyl acetate (200mL) and the mixture was washed with water (100 mL), saturated aqueoussolution sodium bicarbonate (2×100 mL), 10% aqueous solution sodiummetabisulfite (2×100 mL), brine (2×100 mL), dried over sodium sulfate,filtered and the filtrate was evaporated to dryness. The residue wassubjected to column chromatography eluting with hexane:ethyl acetateisocratic mixture (9:1) to produce the title product as a yellow oil(0.8 g, 25%). H-NMR (DMSO-d₆, 400 MHz): δ 8.15 (d, J=8.6 Hz, 1H), 7.65(d, J=2.1 Hz, 1H), 7.42 (dd, J=8.6, 2.1 Hz, 1H), 1.72 (s, 6H).

Example C-5:5-chloro-2-(4-{[4-(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine

To a solution of5-chloro-2-(4-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-methyl}piperidin-1-yl)pyrimidine(129 mg, 0.29 mmol) in dioxane (5 mL) were added2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-6-yl trifluoromethanesulfonate(100 mg, 0.29 mmol), followed by 2M aqueous solution sodium bicarbonate(5 mL) and PdCL₂(dppf) (15 mg). The mixture was stirred and heated to50° C. under argon overnight. The mixture was evaporated, to the residuewas added water (20 mL) and ethyl acetate (40 mL). The ethyl acetatesolution was washed with brine, dried over sodium sulfate, filtered andthe filtrate was evaporated to dryness. The product was subjected tocolumn chromatography on silica gel eluting with a mixture ofhexane:ethyl acetate (gradient 9:1->4:1). The product was obtained as awhite solid (39 mg, 26%). ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.39 (s, 2H),7.89 (d, J=8.2 Hz, 1H), 7.69 (d, J=12.0 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H),7.51 (s, 1H), 7.28 (t, J=8.8 Hz, 1H), 4.63 (d, J=12.4 Hz, 2H), 4.01 (d,J=6.3 Hz, 2H), 2.96 (t, J=12.7 Hz, 2H), 2.21-2.03 (m, 1H), 1.85 (d,J=11.3 Hz, 2H), 1.69 (s, 6H), 1.34-1.16 (m, 2H).

Example C-6: Spiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-ylTrifluoromethanesulfonate

To a solution of 3-hydroxy-4-mercaptophenyl trifluoromethanesulfonate(2.5 g, 9.1 mmol) in toluene (100 mL) was added cyclopentanone (3.8 g,45.5 mmol) and p-toluenesulfonic acid (173 mg, 0.9 mmol). The mixturewas stirred and heated to reflux with Dean-Stark adapter under argon for7 days with TLC control. To the mixture was added ethyl acetate (100 mL)and saturated aqueous solution sodium bicarbonate (50 mL). The organiclayer was separated and washed with brine (100 mL), dried over Na₂SO₄,filtered and the filtrate was evaporated. The residue was subjected toflash chromatography on silica gel eluting with an isocratic mixture ofhexane:ethyl acetate (9:1) to produce the title product as a yellow oil(2.5 g, 82%). ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.40 (d, J=8.5 Hz, 1H), 7.06(d, J=2.4 Hz, 1H), 6.99 (dd, J=8.5, 2.4 Hz, 1H), 2.38-2.28 (m, 2H),2.14-2.03 (m, 2H), 1.86-1.70 (m, 2H).

Example C-7: 3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-ylTrifluoromethane-sulfonate

To a solution of spiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-yltrifluoromethanesulfonate (2.5 g, 7.5 mmol) in acetic acid (40 mL) wasadded 30% aqueous solution hydrogen peroxide (8 mL). The mixture wasstirred at −70° C. for 17 h. To the mixture was added ethyl acetate (200mL) and the mixture was washed with water (100 mL), saturated aqueoussolution sodium bicarbonate (2×100 mL), 10% aqueous solution sodiummetabisulfite (1×100 mL), brine (1×100 mL), dried over sodium sulfateand evaporated. The residue was subjected to flash chromatography onsilica gel eluting with dichloromethane to obtain the title product as awhite solid (1.1 g, 39%). ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.18 (d, J=8.6Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.44 (dd, J=8.6, 2.1 Hz, 1H), 2.48-2.39(m, 2H), 2.08-1.99 (m, 2H), 1.97-1.79 (m, 4H).

Example C-8:5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine

To a solution of5-chloro-2-(4-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-methyl}piperidin-1-yl)pyrimidine(180 mg, 0.4 mmol, 1.1 eq) in dioxane (5 mL) were added3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-yltrifluoromethane-sulfonate (150 mg, 0.4 mmol), 2M aqueous solutionsodium carbonate (0.42 mL) and PdCL₂(dppf) (10 mg, 0.01 mmol). Themixture was stirred and heated to 50° C. overnight. The mixture wasrotary evaporated, to the residue were added water (20 mL) and ethylacetate (40 mL). The organic phase was washed with brine (50 mL), driedover sodium sulfate filtered and the filtrate was evaporated to dryness.The residue was subjected to column chromatography on silica gel elutingwith hexane:ethyl acetate (gradient 5:1-1:1) to produce the titleproduct as a white solid (35 mg, 16%). ¹H-NMR (DMSO-d₆, 400 MHz) δ 8.39(s, 2H), 7.92 (d, J=8.1 Hz, 1H), 7.71 (d, J=12.7 Hz, 1H), 7.58-7.52 (m,3H), 7.3 (t, J=8.5 Hz, 1H), 4.65 (d, J=12.6 Hz, 2H), 4.01 (d, J=6.1 Hz,2H), 2.99 (t, J=12.2 Hz, 2H), 2.48-2.39 (m, 2H), 2.18-2.06 (m, 1H),2.05-1.78 (m, 8H), 1.33-1.17 (m, 2H).

Example C-9: Spiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-ylTrifluoromethanesulfonate

To a solution of 3-hydroxy-4-sulfanylphenyl trifluoromethanesulfonate(3.0 g, 10.9 mmol) in toluene (60 mL) were added cyclohexanone (5.4 g,54.5 mmol) and p-toluenesulfonic acid (190 mg, 1.1 mmol). The mixturewas stirred and heated to reflux with Dean-Stark adapter for 3 days. Tothe mixture was added ethyl acetate (100 mL) and saturated aqueoussolution sodium bicarbonate (50 mL). The organic layer was separated andwashed with brine (50 mL), dried over sodium sulfate, filtered and thefiltrate was evaporated to produce the title product as a brown oil (3.8g, 98%). The product was used in next step without purification. LCMS[M+1]=355.4

Example C-10: 3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-ylTrifluoromethane Sulfonate

To a solution of spiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-yltrifluoromethanesulfonate (3.8 g, 10.9 mmol) in acetic acid (20 mL) wasadded 30% aqueous solution hydrogen peroxide (4 mL). The mixture wasstirred at −70° C. for 17 h. To the mixture was added ethyl acetate (200mL) and the mixture was washed with water (100 mL), saturated solutionsodium bicarbonate (2×100 mL), brine (100 mL), dried over sodiumsulfite, filtered and the filtrate was evaporated to dryness. Theresidue was subjected to column chromatography on silica gel elutingwith dichloromethane to obtain the title product as a white solid (1.3g, 31%). ¹H-NMR (DMSO-d₆, 400 MHz) δ 8.14 (d, J=8.6 Hz, 1H), 7.65 (d,J=2.0 Hz, 1H), 7.41 (dd, J=8.6, 2.0 Hz, 1H), 2.05-1.87 (m, 4H),1.83-1.56 (m, 5H), 1.50-1.35 (m, 1H).

Example C-11:5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine

To a solution of5-chloro-2-(4-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}piperidin-1-yl)pyrimidine(127 mg, 0.28 mmol) in dioxane (5 mL) were added3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-yltrifluoromethanesulfonate (100 mg, 0.26 mmol), 2M aqueous solutionsodium carbonate (0.4 mL) and PdCL₂(dppf) (10 mg, 0.01 mmol). Themixture was stirred and heated to 50° C. overnight. The mixture wasrotary evaporated, to the residue was added water (20 mL) and ethylacetate (40 mL). The organic ethyl phase was washed with brine (50 mL),dried over sodium sulfate, filtered and the filtrate was evaporated todryness. The product was subjected to column chromatography on silicagel to obtain the title product as a white solid (40 mg, 2 7%). ¹H-NMR(DMSO-d₆, 400 MHz) δ 8.39 (s, 2H), 7.87 (d, J=8.3 Hz, 1H), 7.70 (d,J=13.0 Hz, 1H), 7.61-7.48 (m, 3H), 7.27 (t, J=8.6 Hz, 1H), 4.63 (d,J=12.9 Hz, 2H), 4.00 (d, J=6.3 Hz, 2H), 2.96 (t, J=12.0 Hz, 2H),2.20-2.05 (m, 1H), 2.03-1.58 (m, 11H), 1.51-1.36 (m, 1H), 1.32-1.16 (m,2H).

Example C-12: Spiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-ylTrifluoromethanesulfonate

To a solution of 3-hydroxy-4-sulfanylphenyl trifluoromethanesulfonate(3.0 g, 10.9 mmol) in toluene (60 mL) were added cyclobutanone (3.8 g,54.5 mmol) and p-toluenesulfonic acid (190 mg, 1.1 mmol). The mixturewas stirred and heated to reflux with Dean-Stark adapter for 7 days. Tothe mixture were added ethyl acetate (100 mL) and saturated aqueoussolution sodium bicarbomate (50 mL). The organic layer was separated andwashed with brine (50 mL), dried over sodium sulfate and rotaryevaporated to dryness. The product was subjected to columnchromatography on silica gel to afford the title product as a yellow oil(1.3 g, 36%). ¹H-NMR (DMSO-d₆, 400 MHz) δ 7.41 (d, J=8.5 Hz, 1H), 7.13(d, J=2.4 Hz, 1H), 7.01 (dd, J=8.5, 2.4 Hz, 1H), 2.84-2.69 (m, 2H),2.62-2.52 (m, 2H), 1.99-1.86 (m, 1H), 1.85-1.71 (m, 1H).

Example C-13: 3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-ylTrifluoromethane Sulfonate

To a solution of spiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-yltrifluoromethanesulfonate (1.3 g, 3.9 mmol) in acetic acid (20 mL) wasadded 30% aqueous solution hydrogen peroxide (4 mL). The mixture wasstirred at −70° C. for 17 h. To the mixture was added ethyl acetate (200mL) and the mixture was washed with water (100 mL), saturated solutionsodium bicarbomate (2×100 mL), brine (100 mL), dried over sodiumsulfate, filtered and the filtrate was evaporated to dryness. Theresidue was subjected to flash chromatography on silica gel eluting withdichloromethane to produce the title product as a white solid (1.3 g,91%). H-NMR (DMSO-d₆, 400 MHz) δ 8.19 (d, J=8.6 Hz, 1H), 7.67 (d, J=2.1Hz, 1H), 7.43 (dd, J=8.6, 2.1 Hz, 1H), 2.90-2.76 (m, 2H), 2.73-2.59 (m,2H), 2.13-1.96 (m, 1H), 1.84-1.67 (m, 1H).

Example C-14:5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine

To a solution of5-chloro-2-(4-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-methyl}piperidin-1-yl)pyrimidine(137 mg, 0.31 mmol) in dioxane (5 mL) were added3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-yltrifluoromethanesulfonate (100 mg, 0.28 mmol), 2M aqueous solutionsodium bicarbonate (0.42 mL) and PdCL₂(dppf) (10 mg, 0.01 mmol). Themixture was stirred and heated to 50° C. overnight. The mixture wasrotary evaporated, to the residue were added water (20 mL) and ethylacetate (40 mL). The organic phase was washed with brine (50 mL), driedover sodium sulfate, filtered and the filtrate was evaporated todryness. The residue was subjected to column chromatography on silicagel to produce the title product as a white solid (43 mg, 29%). ¹H-NMR(DMSO-d₆, 400 MHz) δ 8.39 (s, 2H), 7.92 (d, J=8.1 Hz, 1H), 7.69 (d,J=12.7 Hz, 1H), 7.60-7.50 (m, 3H), 7.27 (t, J=8.5 Hz, 1H), 4.63 (d,J=12.8 Hz, 2H), 4.00 (d, J=6.2 Hz, 2H), 2.95 (t, J=12.3 Hz, 2H),2.87-2.76 (m, 2H), 2.70-2.57 (m, 2H), 2.19-1.98 (m, 2H), 1.91-1.68 (m,3H), 1.33-1.16 (m, 2H).

VII. Formulations

The present invention also relates to compositions or formulations whichcomprise the prodrug agents for producing the compounds of formula (I)once administered to a patient or subject.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present invention have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

The present teachings also provide pharmaceutical compositions thatinclude at least one compound described herein and one or morepharmaceutically acceptable carriers, excipients, or diluents. Examplesof such carriers are well known to those skilled in the art and can beprepared in accordance with acceptable pharmaceutical procedures, suchas, for example, those described in Remington's Pharmaceutical Sciences,17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,Pa. (1985), the entire disclosure of which is incorporated by referenceherein for all purposes. As used herein, “pharmaceutically acceptable”refers to a substance that is acceptable for use in pharmaceuticalapplications from a toxicological perspective and does not adverselyinteract with the active ingredient. Accordingly, pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable.Supplementary active ingredients can also be incorporated into thepharmaceutical compositions.

Compounds of the present teachings can be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich can also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents, or encapsulating materials. The compoundscan be formulated in conventional manner, for example, in a mannersimilar to that used for known riluzole prodrug agents. Oralformulations containing a compound disclosed herein can comprise anyconventionally used oral form, including tablets, capsules, buccalforms, troches, lozenges and oral liquids, suspensions or solutions. Inpowders, the carrier can be a finely divided solid, which is anadmixture with a finely divided compound. In tablets, a compounddisclosed herein can be mixed with a carrier having the necessarycompression properties in suitable proportions and compacted in theshape and size desired. The powders and tablets can contain up to 99% ofthe compound.

Capsules can contain mixtures of one or more compound(s) disclosedherein with inert filler(s) and/or diluent(s) such as pharmaceuticallyacceptable starches (e.g., corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses (e.g., crystalline andmicrocrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine. Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials, ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited to,metered dose inhalers, breath-operated inhalers, multidose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can beformulated into a liquid composition, a solid composition, or an aerosolcomposition. The liquid composition can include, by way of illustration,one or more compounds of the present teachings dissolved, partiallydissolved, or suspended in one or more pharmaceutically acceptablesolvents and can be administered by, for example, a pump or asqueeze-actuated nebulized spray dispenser. The solvents can be, forexample, isotonic saline or bacteriostatic water. The solid compositioncan be, by way of illustration, a powder preparation including one ormore compounds of the present teachings intermixed with lactose or otherinert powders that are acceptable for intrabronchial use, and can beadministered by, for example, an aerosol dispenser or a device thatbreaks or punctures a capsule encasing the solid composition anddelivers the solid composition for inhalation. The aerosol compositioncan include, by way of illustration, one or more compounds of thepresent teachings, propellants, surfactants, and co-solvents, and can beadministered by, for example, a metered device. The propellants can be achlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or otherpropellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenterally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitably mixed with a surfactant such ashydroxyl-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can sterile and its viscositypermits it to flow through a syringe. The form preferably is stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature.

Compounds described herein can be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations can bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polyethylene glycolsof various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings includingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more riluzoleprodrug according to the present invention and one or more excipients;from about 0.01 mg to about 100 mg of one or more riluzole prodrugaccording to the present invention and one or more excipients; and fromabout 0.1 mg to about 10 mg of one or more riluzole prodrug according tothe present invention; and one or more excipients.

VII. Biological Testing

Biological activity of representative compounds of the disclosure ispresented in Tables 2A, 2B and 2C. The potency of GPR119 receptoragonists was assessed by measuring the stimulation of GPR119-mediatedcAMP production with LANCE Ultra cAMP assay (Perkin Elmer, TRF0264) inCHO cells stably expressing human GPR119 receptor (Chantest, cat.#A633). CHO-GPR119 cells were cultured in DMEM/F12 medium supplementedwith 10% FBS and 1% NEAA at 37° C., 5% CO2, aliquoted and frozen inliquid nitrogen.

For assay, cells were thawed in a water bath at 37° C., washed in Hank'sBalanced Salt Solution (HBSS) and resuspended in Stimulation Buffer 1(SB1) for 30 min: 5 mM HEPES, pH 7.2-7.4, 0.1% BSA in HBSS. The cellswere then recovered in SB2 buffer (1 mM IBMX in SB1) and the cellconcentration was adjusted to 800,000 cells/mL. The ULight-anti-cAMPantibody (Perkin Elmer, TRF0264) was added to the cell suspension makingMix [Cell suspension/4× ULight-anti-cAMP antibodies]. The resulting cellsuspension Mix was plated to 384-well assay plates (Corning, white lowvolume, #3674) 5 L/well. The assay plate was centrifuged 200 g, 5 sec.

Serial dilution (100×) of tested compounds were prepared in DMSO in therange of from 30 nM to 1 mM with half-log step in 384-well plates(Greiner, 781280) using Biomek 2000. 10 test concentrations in tworepeats were prepared for each CRC. It was diluted 50 times in SB1 andeach tested concentration was added to cells in the assay plate—5L/well. The assay plate was incubated 30 minutes at room temperature ona shaker, 250 rpm to allow GPR119 receptor stimulation. The cAMP levelwas determined according to the standard kit supplier protocol(PerkinElmer, cat. #TRF0264).

The stock solution of the Eu-cAMP tracer (Perkin Elmer, TRF0264) wasdiluted 1:100 in cAMP Detection Buffer (Perkin Elmer, TRF0264), making2× working concentration and added to the assay plate, 10 μL per well.Assay plate was centrifuged 180 g, 1 sec. Then the assay plate wasincubated for 60′ at room temperature on shaker, 250 rpm to allow cAMPdetection. The TR-FRET signal was measured at Ex-340 nm/Em-615 andEx-340 nm/Em-665 nm on the reader Tecan M1000. 0% of cAMP stimulationcorresponds to the cells with DMSO only, 100% of cAMP stimulationcorresponds to the cells with 10 M Forskolin. The EC₅₀ value defined asthe concentration of the drug that gives half-maximal response, werecalculated using GraphPad Prizm 5.0 software with forskolin was used asreferences at each test. Entries 1-17 in Table 2A and entries 1-14 inTable 2B show the biological activity of certain representativecompounds using the protocol as described above. For entries 18-25 inTable 2A, entries 15-39 in Table 2B and entries 1-4 in Table 2C, theprotocol was modified to use 500 cells/well, which was found to givebetter Signal/Noise and others statistical parameters. In this modifiedprotocol, the natural ligand, oleoyl ethanolamide had EC50 of 592 nM at100% maximum cAMP stimulation. Forscolin had an EC50 of 28.5 nM at 124%maximum stimulation.

TABLE 2A Biological data for certain compounds of the disclosure EC₅₀ nM(% cAMP Max.relative Entry Example Name to forscolin)  1 A-136-((3-fluoro-4-((1-t-butylpiperidin-4- 833 (75)ylmethoxy)phenyl)-2H-benzo[d][1,3]oxathiole 3,3- dioxide  2 A-144-((4-3,3-dioxido-2H-benzo[d][1,3]oxathiol-6- 86.4 (77)yl)-2-fluorophenyoxy)methyl)-N,N-dimethyl- piperidine-1-carboxamide  3A-15 1-4-((4-3,3-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)- 61.7 (80)2-fluorophenyoxy)methyl)-piperidin-1-yl)-2,2- dimethylpropan-1-one  4A-17 (2-(4-((4-(3,3-dioxido-2H-benzo[d][1,3]oxathiol-6- 10000 (67)yl)-2-fluorophenoxy)methyl)piperidin-1-yl)ethan-1- one  5 A-19((S)-2-amino-1-(4-((4-(3,3-dioxido--2H- 4083 (65)benzo[d][1,3]oxathiol-6-yl)-2- fluorophenoxy)methyl)piperidin-1-yl)-)-3-methylbutan-1-one  6 A-204-((4-3,3,-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)- 10000 (70)2-fluorophenyoxy)methyl)-piperidine-1-carboxamide  7 A-211-4-((4-3,3,-dioxido-2H-benzo[d][1,3]oxathiol-6-yl)- 37 (77)2-fluorophenyoxy)methyl)-piperidin-1-yl)-2- methylpropan-1-one  8 A-23ethyl-2-(4-((4-(3,3-dioxido-2H- 7037 (66) benzo[d][1,3]oxathiol-6-yl)-2-fluorophenyoxy)methyl)-piperidin-1-yl)acetic acid  9 A-246-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4- 2.5 (77)yl)methoxy-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide 10A-29 6-(2-((1-(5-chloropyrimidin-2-yl)piperidin-4- 33.1 (80)yl)methoxy)pyrimidin-5-yl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide 11A-40 5-(4-((1-5-chloropyrimidin-2-yl)piperidin-4- 369 (65)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide 12A-42 6-(4-((1-(1,3,5-triazin-2-yl)piperidin-4-yl)methoxy)- 102 (75)3-fluorophenyl)-2H-benzo[d][1,3]oxathiole 3,3- dioxide 13 A-486-(4-((1-(5-chloropyrimidin-2-yl)azetidin-3- 67 (80)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide 14A-52 6-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5- 24 (81)yl)azetidin-3-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide15 A-58 6-(4-((2-(1-(5-chloropyrimidin-2-yl)piperidin-4- 96 (73)yl)thiazol-5-yl)methoxy)-3-fluorophenyl)-2H-benzo[d][1,3]oxathiole-3,3-dioxide 16 A-596-(3-fluoro-4-((1-(3-isopropyl-1,2,4-oxadiazol-5- 5.4 (77)yl)piperidin-4-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide17 A-65 6-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3- 112.4 (84)fluorophenyl-2H-benzo[d][1,3]oxathiole 3,3-dioxide 18 A-666-(3-fluoro-4-(1-(5-isopropylpyrimidin-2- 19.1 (80)yl)piperidin-4-yl)methoxy)phenyl-2H-benzo[d] [1,3]oxathiole 3,3-dioxide19 A-67 6-(3-fluoro-4-(1-(5-methoxypyrimidin-2- 21.4 (72)yl)piperidin-4-yl)methoxy)phenyl-2H-benzo[d] [1,3]oxathiole 3,3-dioxide20 A-71 (R)-6-(4-((1-(5-ethylpyrimidin-2-yl)pyrrolidin-2- 1690 (51)yl)methoxy)-3-fluorophenyl-2H-benzo[d]oxathiole 3,3-dioxide 21 A-766-(5-((1-(5-ethylpyrimidin-2-yl)piperidin-4- 8.2 (87)yl)methoxy)pyrimidin-2-yl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide 22A-80 (S)-6-(4-((1-(5-ethylpyrimidin-2-yl)pyrrolidin-2- 1312 (25)yl)methoxy)-3-fluorophenyl-2H-benzo[d]oxathiole 3,3-dioxide 23 A-86(S)-6-(4-((1-(5-ethylpyrimidin-2-yl)pyrrolidin-3- 166 (96)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide 24A-89 (S)-6-(4-((1-(5-chloropyrimidin-2-yl)pyrrolidin-3- 46 (93)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide 25A-92 (S)-6-(4-((1-(4-ethylpyrimidin-2-yl)pyrrolidin-3- 58 (90)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3,3-dioxide

TABLE 2B Biological data of certain compounds of the disclosure EC₅₀ nM;Entry Example Name (% cAMP Max.)  1 B-122-(4-((4-benzo[d][1,3]oxathiol-6-yl)-2- 280fluorophenoxy]methyl)piperidin-1-yl)-5-chloropyrimidine  2 B-166-(4-((1-(5-chloropyrimidin-2-yl)piperidin-4- 2.3yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide  3 B-196-(4-((1-(5-ethylpyrimidin-2-yl)methoxy)-3- 4.8fluorophenyl)-2H-benzo[d][1,3]oxathiole-3-oxide  4 B-231-(4-((2-fluoro-4-(3-oxido-2H-benzo[d][1,3]oxathiol- 46.26-yl)phenoxy)methyl)-piperidin-1-yl)-3-methylbutane- 1-one  5 B-246-(3-fluoro-4-((1-(5-methoxypyrimidin-2-yl)piperidin- 2.34-yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole 3- oxide  6 B-256-(4-((1-(4-ethylpyrimidin-2-yl)piperidin-4- 31.8yl)methoxy)-3-(fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide.  7 B-262-(4-((4-benzo[d][1,3]oxathiol-6-yl)-2- >500fluorophenoxy)methyl)piperidin-1-yl)-4-ethylpyrimidine.  8 B-276-(4-((1-(5-ethoxypyrimidin-2-yl)piperidin-4- 4.7yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide  9 B-286-(3-fluoro-4-((1-(5-isopropylpyrimidin-2- 3.0yl)piperidin-4-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3-oxide. 10B-29 6-(3-fluoro-4-((1-(5-(trifluoromethyl)pyridin-2- 52yl)piperidin-4-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3-oxide. 11B-32 (S)-6-(4-((1-(5-chloropyrimidin-2-yl)piperidin-4- 1.2yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 12 B-34(R)-6-(4-((1-(5-chloropyrimidin-2-yl)piperidin-4- 0.9yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 13 B-186-(3-fluoro-4-(piperidin-4-yl)methoxy)phenyl)-2H- >500benzo[d][1,3]oxathiole 3-oxide 14 B-17 tert-butyl4-((2-fluoro-4-(3-oxido-2H- >100benzo[d][1,3]oxathiol-6-yl)phenoxy)methyl) piperidine-1-carboxylate 15B-35 6-(4-((1-(4-ethylpyrimidin-2-yl)piperidin-4- 27.3 (61)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide. 16 B-372-(4-((4-(benzo[d][1,3]oxathiol-6-yl)-2- 365 (79)fluorophenoxy)methyl)piperidin-1-yl)-5-ethylpyrimidine 17 B-382-(4-((4-(benzo[d][1,3]oxathiol-6-yl)-2- 10.5 (78)fluorophenoxy)methyl)piperidin-1-yl)-5-isopropylpyrimidine 18 B-392-(4-((4-(benzo[d][1,3]oxathiol-6-yl)-2- 2900 (64)fluorophenoxy)methyl)piperidin-1-yl)-5-methoxpyrimidine 19 B-401-(4-((4-(benzo[d][1,3]oxathiol-6-yl)-2- 2000 (50)fluorophenoxy)methyl)piperidin-1-yl)-3-methylbutan- 1-one 20 B-45(S)-6-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4- 2.3 (68)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 21 B-46(S)-6-(3-fluroro-4-((1-5-isopropylpyrimidin-2- 10.1 (82)yl)piperidin-4-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 22B-50 (S)-6-(3-fluoro-4-((1-5-methoxypyrimidin-2- 3.7 (66)yl)piperidin-4-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 23B-51 (R)-6-(3-fluoro-4-((1-(5-methoxypyrimidin-2- 40.6 (70)yl)piperidin-4-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 24B-52 (R)-6-(4-((1-(5-ethylpyrimidin-2-yl)piperidin-4- 19.5 (73)yl)methoxy)phenyl)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 25B-53 (R)-6-(3-fluoro-4-((1-(5-isopropylpyrimidin-2- 41 (74)yl)piperidin-4-yl)methoxy)phenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 26B-58 (R)-6-(2-((1-(5-chloropyridin-2-yl)piperidin-4- 107 (66)yl)methoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole 3-oxide 27 B-59(S)-6-(4-((1-(5-chloropyrimidin-2-yl)piperidin-4- 1.7 (70)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 28 B-62(S)-6-(2-((1-(5-chloropyrimidin-2-yl)piperidin-4- 43.5 (66)yl)methoxy)pyrimidin-5-yl)-2H-benzo[d][1,3]oxathiole 3-oxide 29 B-676-(4-(((R)-1-(5-ethylpyrimidin-2-yl)pyrrolidin-3- 54 (74)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 30 B-69(R)-2-(3-((4-benzo[d][1,3]oxathiol-6-yl)-2- >10,000fluorophenoxy)methyl)pyrrolidin-1-yl)-5- ethylpyrimidine 31 B-75(S)-6-(4-(((S)-1-(5-ethylpyrimidin-2-yl)pyrrolidin-3- 17.7 (88)yl)methoxy)-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide 32 B-76(R)-6-(4-(((S)-1-(5-ethylpyrimidin-2-yl)pyrrolidin-3- 20.5 (80)yl)methoxy-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide 33 B-77(S)-6-(4-(((R)-1-(5-ethylpyrimidin-2-yl)pyrrolidin-3- 32.5 (81)yl)methoxy-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide 34 B-78(R)-6-(4-(((R)-1-(5-ethylpyrimidin-2-yl)pyrrolidin-3- 115 (72)yl)methoxy-3-flurophenyl)-2H-benzo[d][1,3]oxathiole 3-oxide 35 B-81(S)-6-(-4-(((S)-1-(5-chloropyrimidin-2-yl)pyrrolidin-3- 30 (95)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 36 B-84(S)-6-(4-(((S)-1-(4-ethylpyrimidin-2-yl)pyrrolidine-3- 31.5 (92)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 37 B-85(R)-6-(4-(((S)-1-(4-ethylpyrimidin-2-yl)pyrrolidine-3- 13 (64)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 38 B-86(R)-6-(4-(((S)-1-(5-chloropyrimidin-2-yl)pyrrolidine-3- 4.6 (93)yl)methoxy)-3-fluorophenyl)-2H- benzo[d][1,3]oxathiole 3-oxide 39 B-91(S)-6-(4-(((S)-1-(5-ethylpyrimidin-2-yl)pyrrolidine-3- 10.3 (93)yl)methoxy)phenyl)-2H-benzo[d][1,3]oxathiole 3- oxide

TABLE 2C Biological data of certain compounds of formula (I) in thedisclosure EC₅₀ nM (% cAMP Max.relative Entry Example Name to forscolin)1 C-5 5-chloro-2-(4-{[4-(2,2-dimethyl-3,3- 68.6 (81)dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)py- rimidine 2 C-85-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3- 114 (66)benzoxathiole-2,1′-cyclopentan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1- yl)pyrimidine 3 C-115-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3- 33.0 (25)benzoxathiole-2,1′-cyclohexan-6-yl)-2- fluorophenoxy]methyl}piperidin-1-yl)pyrimidine 4 C-14 5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3- 29.8 (67)benzoxathiole-2,1′-cyclobutan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1- yl)pyrimidine

Certain test compounds were evaluated using the PathHunter® β-arrestinassay, which monitors the activation of GPR119 in a homogenous,non-imaging assay format using the enzyme fragment complementation (EFC)technology (DiscoverX Corporation, Fremont, Calif. U.S.A.;www.discoverx.com) with β-galactosidase as the functional reporter.These results are shown in Table

TABLE 3 Biological data of certain compounds of the disclosure EC₅₀ nM;Entry Example Name ( % cAMP Max.) 1 B-34(R)-6-(4-((1-(5-chloropyrimidin-2- 35.7 (172)yl)piperidin-4-yl)methoxy)-3-fluoro- phenyl)-2H-benzo[d][1,3]oxathiole3-oxide 2 B-46 (S)-6-(3-fluroro-4-((1-5-isopropyl- 7.9 (164)pyrimidin-2-yl)piperidin-4-yl)meth- oxy)phenyl)-2H-benzo[d][1,3]oxa-thiole 3-oxide 3 B-50 (S)-6-(3-fluoro-4-((1-5-methoxy- 16.4 (169)pyrimidin-2-yl)piperidin-4-yl)meth- oxy)phenyl)-2H-benzo[d][1,3]oxa-thiole 3-oxide 4 B-59 (S)-6-(4-((1-(5-chloropyrimidin-2- 6.7 (175)yl)piperidin-4-yl)methoxy)-3-fluoro- phenyl)-2H-benzo[d][1,3]oxa- thiole3-oxide 5 B-75 (S)-6-(4-(((S)-1-(5-ethylpyrimidin-2- 60 (190)yl)pyrrolidin-3-yl)methoxy)-3-fluro- phenyl)-2H-benzo[d][1,3]oxa- thiole3-oxide 6 B-84 (S)-6-(4-(((S)-1-(4-ethylpyrimidin-2- 567 (117)yl)pyrrolidine-3-yl)methoxy)-3-fluoro- phenyl)-2H-benzo[d][1,3]oxathiole3-oxide 7 B-85 (R)-6-(4-(((S)-1-(4-ethylpyrimidin-2- 657 (73)yl)pyrrolidine-3-yl)methoxy-3-fluoro- phenyl)-2H-benzo[d][1,3]oxathiole3-oxide 8 B-86 (R)-6-(4-(((S)-1-(5-chloropyrimidin-2- 108 (133)yl)pyrrolidine-3-yl)methoxy)-3-fluoro phenyl)-2H-benzo[d][1,3]oxathiole3-oxide 9 B-91 (S)-6-(4-(((S)-1-(5-ethylpyrimidin-2- 222 (155)yl)pyrrolidine-3-yl)methoxy)phenyl)- 2H-benzo[d][1,3]oxathiole 3-oxide

Certain compounds and compositions disclosed herein are therefore usefulas GPR119 receptor activity modulators (e.g. as full or partialagonists), e.g. certain compounds may be for use in vitro, oralternatively certain compounds may be for use in vivo. Certaincompounds and compositions disclosed herein may be useful as full orpartial agonists in vitro. Certain compounds and compositions disclosedherein may be useful as full or partial agonists of GPR119 in humans ornon-human animals (e.g. rodents and non-human primates). There is thusdisclosed a method of modulating the activity of a GPR119 receptor (e.g.activation of the receptor) comprising contacting a GPR119 receptor invitro, or alternatively in vivo, with a compound or composition asdefined herein (e.g. a compound of any one of formula I to XXX, or anyactivity modulator compound shown in any one of Example C-1 to C-91).

What is claimed is:
 1. A compound having formula (I):

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (I), or a prodrug or complex thereof,wherein: X¹ is O and X² is S, SO or SO₂; or X² is O and X¹ is S, SO orSO₂; X³ is CH, CF and N; each X⁴ is independently CH and N; A is

R is

R¹ is hydrogen, C(O)O-tert-butyl or

R^(2a) is hydrogen or C₁₋₆ alkyl; R^(2b) is hydrogen or C₁₋₆ alkyl; R³is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b), CH₂C(O)OR^(10a),

R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b),

R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R⁹, C(O)OR¹⁰,C(O)NR^(10a)R^(10b),

R⁶ is

NHR¹¹ or CH₂NHR¹²; R^(7a) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇branched alkyl, C₁₋₆ haloalkyl or C₁₋₆ alkoxy; R^(7b) is hydrogen,halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆ haloalkyl or C₁₋₆ alkoxy;R^(7c) is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇ branched alkyl, C₁₋₆haloalkyl or C₁₋₆ alkoxy; R⁸ is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₇branched alkyl or C₃₋₇ cycloalkyl; R⁹ is C₁₋₆ alkyl, C₃₋₇ branched alkylor

R¹⁰ is C₁₋₆ alkyl or C₃₋₇ branched alkyl; R^(10a) is hydrogen, C₁₋₆alkyl or C₃₋₇ branched alkyl; R^(10b) is hydrogen, C₁₋₆ alkyl or C₃₋₇branched alkyl; R¹¹ is

R¹² is

each R^(13a) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇ branchedalkyl; each R^(13b) is independently hydrogen, C₁₋₆ alkyl or C₃₋₇branched alkyl; each R^(14a) is independently hydrogen, C₁₋₆ alkyl, C₃₋₇branched alkyl or C(O)O-tert-butyl; each R^(14b) is independentlyhydrogen, C₁₋₆ alkyl or C₃₋₇ branched alkyl; X⁵ is N or CR^(7b); n¹ is 1or 2; n² is 1 or 2; and m is 1, 2, 3, 4, 5, 6 or 7; each of X⁶, X^(6′)and X^(6″) is independently H, halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ hydroxyalkyl, or C₁₋₃(O)NR^(15a)R^(15b); each of X⁷ andX^(7′) is independently hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl,C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl orC₁₋₃(O)NR^(15a)R^(15b), or both X⁷ and X^(7′) together form C₃₋₆cycloalkyl or a heterocycle ring having 3-6 carbons and 0 or 1 oxygen,sulphur or nitrogen atom in the ring, wherein each carbon ring atom ofthe C₃₋₆ cycloalkyl or the heterocycle is independently substituted withhydrogen, C₁₋₃ alkyl, hydroxyl, halogen, amino, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ hydroxyalkyl or C₁₋₃(O)NR^(15a)R^(15b); when each of X⁶,X^(6′) and X^(6″) is hydrogen, at least X⁷ or X^(7′) is not hydrogen;when both X⁷ and X^(7′) are hydrogen, at least one of X⁶, X^(6′) andX^(6″) is not hydrogen; and each of R^(15a) and R^(15b) is independentlyhydrogen, C₁₋₃ alkyl or C₃ branched alkyl.
 2. The compound of claim 1,wherein one, two or three of X⁶, X^(6′) and X^(6″) are fluorine,optionally wherein X⁶, X^(6′) and X^(6″) are: F, H and H, respectively;H, F and H, respectively; or H, H and F, respectively.
 3. (canceled) 4.The compound of claim 1, wherein X⁶, X^(6′) and X^(6″) are each H. 5.The compound of claim 1, wherein A is


6. The compound of claim 5, wherein R is


7. The compound of claim 6, wherein R is

and R³ is


8. The compound of claim 6, wherein R is

and wherein R⁴ is


9. (canceled)
 10. The compound of claim 6, wherein R is

and R⁵ is


11. The compound of claim 1, wherein A is

optionally wherein R¹ is


12. (canceled)
 13. The compound of claim 1, wherein A is


14. The compound of claim 1, wherein both of X⁷ and X^(7′) are hydrogenand at least one of X⁶, X^(6′) and X^(6″) is not hydrogen.
 15. Thecompound of claim 1, wherein both of X⁷ and X^(7′) are CH₃.
 16. Thecompound of claim 1, wherein at least one of X⁷ and X^(7′) is halogen.17. The compound of claim 1, having: formula (II) or an enantiomer,diastereomer, hydrate, solvate, or pharmaceutically acceptable salt offormula (II), or a complex thereof

formula (III) or an enantiomer, diastereomer, hydrate, solvate, orpharmaceutically acceptable salt of formula (III), or a complex thereof

formula (IV) or an enantiomer, diastereomer, hydrate, solvate, orpharmaceutically acceptable salt of formula (IV), or a complex thereof

formula (V) or an enantiomer, diastereomer, hydrate, solvate, orpharmaceutically acceptable salt of formula (V), or a complex thereof

wherein X⁸ is NH or O; formula (VI) or an enantiomer, diastereomer,hydrate, solvate, or pharmaceutically acceptable salt of formula (VI),or a complex thereof

wherein: one X⁸ is NH or O; and one X⁸ is CH₂; or formula (VII) or anenantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt of formula (VII), or a complex thereof

wherein one X⁸ is NH or O, and wherein each of two X⁸ is CH₂. 18-22.(canceled)
 23. The compound of claim 1, wherein both X⁷ and X^(7′)together form

wherein R is H or C₁₋₃ alkyl.
 24. The compound of claim 1, wherein: X¹is O and X² is SO₂; X¹ is SO₂ and X² is O; X¹ is O and X² is SO; X¹ isSO and X² is O; X¹ is O and X² is S; or X¹ is S and X² is O. 25-50.(canceled)
 51. The compound of claim 1, wherein X³ is selected from thegroup consisting of CF and N.
 52. A compound, which is:5-chloro-2-(4-{[4-(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine;5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine;5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine;or5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine.53. A pharmaceutical composition comprising the compound of claim 1 anda pharmaceutically acceptable excipient and/or an anti-diabetic agent.54. A method of treating a disease associated with GPR119 dysregulation,said method comprising administering to a subject (i): the compound ofclaim 1; or (ii) a pharmaceutical composition comprising the compoundand a pharmaceutically acceptable excipient and/or an anti-diabeticagent optionally wherein the disease is Type 2 diabetes mellitus. 55-58.(canceled)